10

Pneumocystis carinii and Parasitic Infections in the Immunocompromised Host

JAY ALAN FISHMAN

1. Introduction either fail to establish infection or overwhelm the host. The effects of immune compromise on the manifesta• International travel and shifting patterns of immigration tions of infections due to parasites are defined by the have increased the importance of awareness of the major "natural" mode of evasionlinteraction with the host's im• clinical syndromes associated with infections due to mune system and by the nature of the immune lesion(s) parasites. In the immunocompromised individual, life• (see Table 1). While P. carinii can no longer be consid• threatening infection may emerge decades after a forgot• ered a protozoan parasite, the great morbidity due to this ten exposure in an endemic area. Most clinicians have organism in patients with AIDS illustrates the effects of some familiarity with the major clinical syndromes asso• immune compromise on the development of disease due ciated with malaria, Chagas' disease, giardiasis, ame• to an organism of low native virulence. In the past, so• biasis, or the helminthic diseases. The spectrum of im• phisticated diagnostic and therapeutic technology has not mune deficits is almost as broad as the tens of thousands been available in the areas of greatest prevalence of para• of species of parasites to which humans are exposed. sitic disease. However, increasing numbers of patients However, prior to the recognition of the acquired immu• with immune compromise due to AIDS, cancer chemo• nodeficiency syndrome (AIDS), important parasites in therapy, immunosuppressive therapy, and malnutrition, the immunocompromised host were largely limited to coupled with increased travel and interest in parasitic infections with Toxoplasma gondii, Pneumocystis car• diseases, have increased the frequency and the recogni• inii, Strongyloides stercoralis, and occasionally babesi• tion of infections due to these organisms. osis or malaria related to transfusions in splenectomized patients. Many new human parasites, both pathogens 1.1. Parasite Factors: Development and nonpathogens of the nonnal host, must now be add• and Distribution ed to this list [see Table 1 (Section 1.2)]. The presence, progression, and manifestations of some parasitic dis• Each year, parasites cause over 2 billion infections eases are altered by immune compromise. These organ• worldwide. It is predictable that some of these infections isms provide the focus of this discussion. occur in individuals immunocompromised by malnutri• Successful parasitism is defined by the adaptation of tion or underlying disease (notably cancer or AIDS) or an organism to the host environment. In the absence of by immunosuppressive therapy. A history of travel to an immunologic niche for the organism, the parasite will endemic areas (recent or distant) or of exposures to food, water, animals, blood products, or other vectors of para• sitic disease may provide a source of acute or reactivated infection during immune suppression. Some infections JAY ALAN FISHMAN • Infectious Disease Unit, Medical are prevalent in subgroups of immunologically nonnal Service and Transplantation Unit, Surgical Service, Massa• hosts in developed regions. Homosexual males have an chusetts General Hospital, Harvard Medical School, Boston, increased incidence of infections with intestinal parasites Massachusetts 02114. (including Trichuris and pathogenic Entamoeba histo• Clinical Approach to Infection ill the Compromised Host (Third Edi• tion), edited by Robert H. Rubin and Lowell S. Young. Plenum Medi• lytica, Giardia, Strongyloides) and nonpathogenic proto• cal Book Company, New York, 1994. zoa. Infection with other pathogens (cytomegalovirus,

275

R. H. Rubin et al. (eds.), Clinical Approach to Infection in the Compromised Host © Plenum Publishing Corporation 1994 276 CHAPTER 10

Salmonella, Shigella) in this population may contribute ited by the size of the initial inoculum. The burden of to the pathogenesis or severity of concomitant infections. this latter group of organisms cannot increase during the Day care and chronic care centers are common sources course of disease. As a result, helminths (worms) tend to for infections with Giardia, amebae, and Crypto~po­ cause mechanical obstruction due to size and location ridium. and are generally limited to the gastrointestinal (01) The parasite's life cycle determines the nature and tract. Accelerated growth of protozoans derepressed by duration of the exposure of the organism to the host's immune dysfunction produces systemic disease that re• immune system (see Section 2.1) and the clinical mani• flects the initial sites (organs) of infection and the ulti• festations of infection. Because the immune system in• mate location of reemergent disease. With other para• terferes with the completion of the parasite life cycle, sites, the pattern of disease (e.g., invasiveness) changes immune suppression has the greatest effect on the growth with immune suppression. of organisms that replicate within the human host. The protozoa as a group have the capability of completing 1.2. Host-Parasite Interactions and Mechanisms their life cycle within the human host. Depression of of Immune Evasion immune barriers may predispose to invasive disease by gastrointestinal parasites, as in amebiasis, or to dissem• Significant infections due to parasites occur when ination of intracellular organisms that overwhelm the retic• the balance between host protective mechanisms and uloendothelial system in the absence of cytokines (inter• parasite growth is disrupted. Specific immune lesions leuken-2 and interferon-'Y), as can be seen in some cases (e.g., hypogammaglobulinemia) may not predispose to of leishmaniasis in AIDS. Similar predisposition to in• parasites normally controlled by other mechanisms (e.g., fection due to latent protozoans accounts for most infec• T lymphocytes). Some infections (e.g., malaria, ame• tions due to P. carinii and T. gondii. Strongyloides ster• bae) are not appreciably exacerbated by immune sup• coratis is unusual as a nematode because of its ability to pression. A second group causes little or no disease (sub• complete its life cycle within the human host. Thus, it is clinical or mild, commensal, or latent infection) until predictable that the manifestations of infection due to activated in the setting of immune compromise. Some of this organism would be exacerbated by immune suppres• the most "successful" parasites have the ability to'· avoid sion as it is not for other worms. detection or killing or both by the immune system. Some By contrast, the intensity of infection by organisms of the common mechanisms of immune evasion are list• that require both development outside the host and sub• ed in Table 1. A number of parasites are resistant to sequent penetration (often ingestion) into the host is lim- antibody- and complement-mediated lysis (e.g., Schis-

TABLE 1. Mechanisms for the Evasion of the Host Immune Response in Parasites

Host response Mediator Mechanism Examples

Nonspecific inflammation Anti-inflammatory molecules Amebae, T. taeniaefarmis Humoral Complement Surface resistance T. cruzi. schistosomes, Leishmania Humoral Antibody Shedding antigen Trichinella. schistosomes Antigenic variation Trypanosomes, Giardia Antigenic mimicry Schistosomcs Antibody destruction Filaria, T. cruzi Host antigen coat P. carinii. T. vivax Polyclonal stimulation Trypanosomes Cellular Macrophage Block fusion/acidification T. gOlldii Phagocytosis Escape phagolysosome T cruzi Evade oxidative burst T. gOlldii. L. donol'alli Alter macrophage function" Leishmania. T. brucei (decreased IL-\, MHC) Eosinophil Inhibit attachment Schistosomes None Privileged site Escape into gut Ascarius. hookworms Eye Ochocercus Lymphoblast Theileria Liver Malaria Muscle Sarcocystis Intestinal epithelia Coccidia aOL-l) lnterleukin 1: (MHC) gene products of the major histocompatibility Incus. PNEUMOCYSTIS CARlNll AND PARASITIC INFECTIONS 277

TABLE 2. Parasitic Infections of Importance in the 1.3. Missing Infections in Acquired Immunocompromised Host" Immunodeficiency Syndrome

Mechanism Organisms A subgroup of common parasitic infections have not increased substantially in frequency or severity in indi• Neutrophil inflammation P. cariniih viduals infected with the human immunodeficiency virus Humoral immunity C. lamblia, Cryptospuridillm Cellular immunity P. carinii, b T gondii, C"ptosporidillm, (HI V). 5 These infections include S. stercoralis, malaria, Strongvloides, Leishmania, Micro• E. histolytica, and trypanosomiasis. Unrecognized or sporidia. Isospora belli, C. lamblia, unreported infections (especially Strongyloides) may ac• E. histolytica count for some of the reduction in expected infection aThis table does not list common parasitic infections that occur in frequencies. However, the immune lesion(s) seen in immunocompromised patients from endemic regions or in "at risk" AIDS may not include some relevant immune defenses populations but are not increased in severity or frequency. I>pneumoc .... ·stis carinii is included for purposes of this discussion. but is not (e.g., of the intestinal mucosa). These organisms cause now considered to be a protozoan parasite. significant disease in other immunocompromised hosts. Multiple potential pathogens are often found in diarrheal stools from individuals infected with HIY. 6,7 The organ• tosoma, Trypanosoma cruzi).1-3 Others vary or shed sur• ism(s) causing disease (e.g., cytomegalovirus micro• face antigens to avoid detection. Still others become sporidia, or Cryptosporidia) may be demonstrated micro• coated with host proteins to diminish immune detection. scopically in the small intestine but remain undetected in Filaria, Leishmania, and trypanosomes are capable of stool samples. Because of the importance of diarrheal inducing defects in cell-mediated immunity.4 Patients illness in AIDS patients, particularly in Africa (i.e., with defects in cell-mediated immunity are particularly "slim disease") and in homosexual males, it is important susceptible to infections due to Pneumocystis, T gondii, clinically to separate pathogenic organisms from the Cryptosporidium species, Leishmania species, and S. common commensal organisms, which include C. stercoralis (see Table 2). Subgroups of organisms of par• lamblia, E. histolytica, and Blastocystis hominis, as well ticular importance to the compromised host are the intra• as viral, bacterial, and fungal pathogens. cellular parasites (T gondii, Leishmania, and T cruzi) that evade killing by host macrophages. All share the need to evade the humoral (complement and antibody) 2. Pneumocystis carinii immune response and intracellular oxidative killing mechanisms prior to establishing intracellular residence. Despite the description of Pneumocystis carinii in Perhaps the best example of the interaction of a 1909 by Chagas and again in 1910 by Carini, P. carinii parasite with the immune system is that of Leishmania was not recognized as a pathogen of humans until 1942. species. The manifestations of cutaneous leishmaniasis The first clear association of P. carinii with human dis• (L. mexicana complex, L. braziliensis complex, L. tropi• ease was in 1951, when Vanek and lirovec8 found the ca, L. major) range from localized cutaneous disease to organism in the lungs of malnourished infants and neo• diffuse cutaneous or mucocutaneous ("espundia") in• nates with an "interstitial plasma cell pneumonitis. "'1-16 volvement. Disseminated disease (visceral leishmaniasis This unusual disease had been associated with epidemics or kala-azar) involving the liver, spleen, bone marrow, of pneumonia in malnourished children in the aftermath and reticuloendothelial system also occurs (L. donovani, of each of the major wars.13.17.18 Pneumocystis carinii L. chagasi, L. infantum). In the presence of a normal was first recognized in patients receiving corticosteroids cell-mediated immune response and in the absence of and chemotherapeutic drugs in the 1950s with clusters of specific antibody, cutaneous lesions often heal sponta• cases in clinical oncology centers in the 1970sY·lo,18-25 neously. Patients with diffuse cutaneous leishmaniasis The emergence of P. carinii as a major pathogen of generally have high levels of specific antibody without individuals with AIDS has revolutionized the approach antigen-specific delayed-type hypersensitivity (DTH). to diagnosis and management of patients with Pneu• Relapsing (recidivans) and mucocutaneous disease oc• mocystis pneumonia. 26- 3o Molecular studies of the or• curs in the presence of DTH, but macrophage dysfunc• ganisms have also suggested that Pneumocystis may be tion is suggested by the paucity of granulomata in af• more closely related to the fungi than to the protozoan fected tissues. Visceral disease occurs in the absence of parasites. 31 - 34 Such molecular studies, new animal mod• cell-mediated immunity and in the presence of specific els, and the increasing number of patients with Pnell• antibody. Fatal disease has been reported in AIDS pa• mocystis pneumonia in AIDS have added impetus to im• tients in the setting of marked T-Iymphocyte deficiency. provements in the care of patients with this disease. 278 CHAPTER 10 /TJ\\~~" ([oj @(o) :. @ ASEXUAL SEXUAL \. REPLICAT I ON~ REPLICATION ,

W~6'D PRECYSTS @ (~~}:=;\Y l0 i 7 ~ @ tp~) 00 ~t 0'$ :i- FIGURE 1. Life cycle of Pneumocvstis carinii. Both sexual and asexual reproduction have been postulated. TROPHOZOITES Glucan synthesis is necessary for cyst wall formation. Only the cyst form stains with methenamine~silver stains.

2.1. The Organism: Taxonomy and Life Cycle ganisms 2-6 f.Lm in diameter with pseudopodia and a dense covering of small filopodia ("tubular expansions") The taxonomic position of P. carinii remains uncer• of uncertain functions. 37~39 The trophozoite contains a tain. The organism bears resemblance to both the fungi nucleolus, nuclear pores, primitive mitochondria, endo• and the protozoan parasites.26.31~34 The appearance of plasmic reticulum (ER), and ribosomes, but apparently the organism in vivo is most similar to that of the proto• lacks Golgi, ftagellae, and cilia. The "cyst" form is a zoa, including the thick-walled cyst form with multiple thick-walled (l00-200 nm) sphere 4-7 f.Lm in diameter internal sporozoites and the small, thin-walled tro• that contains up to eight internal daughter cells called phozoites (Fig. 1). Antibiotics used to treat protozoan "intracystic bodies" or "sporozoites." The cyst wall has infections including T. gondii and malaria have been suc• an electron-lucent middle layer that is stained by the cessful in the treatment of Pneumocystis pneumonia. By methenamine-silver technique and is absent in tro• contrast, the cyst wall contains [3-1 ,3-glucans and stains phozoites (Fig. 2). Thus, the silver stains commonly with both methenamine-silver and the periodic acid• used to detect P. carinii in tissue samples or in sputum Schiff (PAS) stains typically used for fungi. Two impor• samples will detect only 3-10% of the organism burden. tant enzymes of folate metabolism (dihydrofolate reduc• The sporozoites each have a nucleus, mitochondrion, tase and thymidylate synthase) are encoded on separate and large numbers of ribosomes and ER. Intermediate genes encoding distinct proteins. This contrasts with one forms between the trophozoite and the cysts have been gene encoding a bifunctional protein (both enzymatic termed "precysts." These have an oval shape, intermedi• activities) in the protozoa. 35 .36 The airborne spread of ate cell wall thickness, loss of tubular expansions, and infection supports identification with the dimorphic fun• occasionally a nuclear "synaptonemal complex" consis• gi. Phylogenetic mapping based on ribosomal messenger tent with meiotic division. It is postulated that the eight RNA sequences also places the organism more closely daughter nuclei are the product of two meiotic divisions with the yeasts than with the protozoa. 3 I.34 On the basis and one mitosis (see Fig. 1). While some reports exist of of the common derivation of both the fungi and the pro• intracytoplasmic location for P. carinii, this observation tozoa from the classic Protista, it may well be that Pneu• has not been common. In general, the organisms are mocystis represents a unique phylogenetic niche and will embedded in a layer of alveolar material along the bear relationships with mUltiple groups of organisms in• epithelial surface. Some organisms are seen surrounded cluding the fungi, protozoa, algae, and slime molds by cytoplasmic protrusions from type I epithelial cells (Dictyostelium). Further genetic data may clarify these and within vesicles of alveolar macrophages. The tro• questions. phozoites are often closely adherent to the epithelial sur• Pneumocystis carinii is an extracellular organism face with interdigitation of the cell membranes. 38 •4o In that appears in three forms in the pulmonary alveolus areas of epithelial cell loss, organisms adhere to the (Fig. 1). Up to 95% of the organisms are trophozoites: basement membrane. The mechanisms of cell injury and motile, pleomorphic, thin-walled (20 nm) nucleated or- the nature of the interaction between the lung cells and P. PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 279

B

FIGURE 2. (A) Hematoxylin- eosin stain of Plleumocystis-infected lung demonstrating pathognomonic intra-alveolar "frothy" material, interstitial widening, and minimal inflammatory cell infiltration. The biopsy was obtained from a patient with AIDS. (B) Induced sputum examination reveals multiple cyst forms stained with a rapid methenamine- silver stain. Immunofluorescent staining is preferred for rapidity and because both cyst and trophozoite forms of P. carinii are detected. 280 CHAPTER 10 carinii are unknown. Productive culture in vitro has not Clusters of infection in clinical oncology centers and been achieved without cell contact. serologic studies support the aerosol transmission of in• The absence of a continuous ill vitro cultivation sys• fection from environmental or human sources or both. tem for P. carillii has made studies of the life cycle Recent studies using the corticosteroid-treated animal difficult. 38,41,42 Observation of the organism in tissue model of infection suggest that few organisms « 100 sections or with a feeder layer of mammalian tissue cul• cysts) are needed to cause infection in the Immu• ture cells ill vitro suggest the scheme diagrammed in Fig. nocompromised host. 1. Both sexual and asexual replication have been postu• The role of T lymphocytes in protection against lated. Trophozoites mature into the aforementioned early infection is best illustrated by the use of cyclosporin A in cyst forms C'precysts") with up to eight visible nuclei rats and the use of antibodies to T-helper lymphocytes and a thick outer cell wall. It is the cell wall maturation (CD4+) in mice to deplete the host immune re• step that appears to be blocked by inhibitors of glucan sponse. 53 ,54 The protective effect of the passive transfer synthesis. This group of glucan synthase inhibitors (echi• of T lymphocytes in the mouse model also supports the nocandins and others) blocks the production of cysts ill primacy of the T-cell response in prevention of P. carinii vivo and inhibits increases in organism burden during infection.55,56 Augmentation of the macrophage re• exposure to these agents. Cell membranes form around sponse using interferon-), (lFN-)') appears to reduce the each of the internal nuclei of cysts, forming the afore• amount of antibiotic needed to clear infection. 57 ,58 The mentioned internal "sporozoites." The cysts rupture to roles of colony-stimulating factors [granulocyte- and release immature trophozoites of a variety of shapes and granulocyte-macrophage-stimulating factors (G-, GM-, sizes to restart the cycle. In vitro cultivation for periods and M-CSF)) in the clearance of infection are not yet up to 10 days has been achieved using rat-lung-derived known. Passive immunization with monoclonal anti• organisms cultured on a variety of mammalian cell lines. bodies is partially protective against P. carinii infection, Despite extensive efforts, the system has been improved suggesting a role for both cellular and humoral immune very little since the first in vitro cultivation by Pifer et mechanisms. al. 41,46 and Latorre et al. 45 in 1977. 43 ,44 Reports of suc• A major role for animal models has been the evalua• cessful axenic culture of organisms using fungal media tion of therapies for the treatment of Pneumocystis pneu• have not provided growth beyond 48-72 hr after inocula• monia. The efficacy of antibiotics in the rat model has tion.42 The culture systems have assisted in "cleaning been shown to correlate with successful outcome in clini• up" preparations of organisms that are contaminated by cal applications. Most of the new agents available for host lung cells and proteins. Viability tests for P. carillii treatment of P. carinii (aerosolized pentamidine, clinda• are in their infancy. Reviews of the biology of P. carinii mycin-primaquine, BW566c80, dapsone-trimethoprim, have been published. 25 ,26,40,43 glucan synthase inhibitors, azithromycin, trimetrexate, erythromycin-sulfa) have been developed and tested using the rat and mouse models. 2.2. Epidemiology A limited number of antigens have been detected on 2.2.1. Animal Studies and Serology P. carinii. 59-63 Monoclonal antisera raised to these moieties have been useful in the development of immu• The natural reservoir for P. carinii is unknown. The nofluorescent staining of clinical specimens for the diag• association of protein-calorie malnutrition and of im• nosis of P. carinii pneumonia. The major antigens de• mune suppression with the development of P. carinii tected in human organisms by Western immunoblotting pneumonitis has been documented in the rat and mouse are of molecular weights 110-116,50-55,60-65,35- models of this disease. 40 ,44,47,48 The rat model has 45, and 22-25 kDa. These molecules are poorly soluble changed little since the description of the induction of P. and very "sticky," accounting for the low level of anti• carinii pneumonia in animals treated with cortisone ace• genemia seen in Pneumocystis pneumonia and the tate by Weller in 1955 and by Frenkel et al. 50 in clumping of organisms. A number of other antigens are 1966. 49 ,51 The animal model has been modified to utilize variably detected. There is variation in the pattern of "virus-free" rats using transtracheal inoculation of P. glycosylation of P. carinii antigens isolated from differ• carinii; this modification results in fewer infections in ent species. The role of these antigens in immunity to P. these immunosuppressed animals due to other pathogens carinii is not known. 60 ,63,65 As was noted, passive trans• and a more consistent level of infection. 52 These studies fer of T cells, but not serum, from immune animals is suggested that pneumonitis was the result of the emer• protective against Pneumocystis infection.55 Up to 87% gence of latent infection during immune suppression. of adults have lymphocyte proliferation in response to Aerosol transmission of the organism has also been dem• stimulation with P. carinii antigens. 64-66 Solubilized onstrated in the animal model by Hughes and others. (and particulate) glycoproteins of the 55-60 kDa and PNEUMOCYSTIS CARlNlI AND PARASITIC INFECTIONS 281

100-116 kDa ranges stimulate T-Iymphocyte prolifera• The absence of immunity to P. carinii in babies is illus• tion from sensitized hosts60,()4 In the lungs, antigenic trated in children with congenital HIV infection. These processing by accessory cells (dendritic cells and macro• patients can be expected to survive for less than 1 year. phages) is needed for the generation of Pnclilnocystis• Patients developing AIDS or HIV infection after 1 year specific T-cell proliferation, IFN-'Y and Dapsone appear of age do somewhat better. Both the malnourished in• to enhance intracellular killing of P, carinii by macro• fants and congenitally infected AIDS patients develop phages, Opsonization by immune serum is not essential, Pncllmocystis pneumonia on average by 6 months of age. but improves phagocytosis by nonimmune macro• Pnclilnocystis carinii is an organism of low native phages,67 The organisms are subsequently degraded virulence. Apparent enhanced virulence of P. carinii in without evidence of intracellular replication, Infection some individuals may be a function of co infection alone, by HIV decreases internalization but not adhesion of p, immune suppression due to coexistent viral (CMV, HIV) carinii to alveolar macrophages, The production of cyto• infection, or the possibility that coinfection with certain kines (TNF-cx and IL-I ~) by macrophages in response to agents may enhance the virulence of infection due to P. P. carinii is also blocked by infcction with HIY. carinii. The association of cytomegalovirus (CMV) with Pnclllllocystis is commonly observed73,74 This associa• 2.2.2. The Susceptible Host tion is due largely to the frequency of CMV infection in the population of immunocompromised individuals. PnClilnocvstis has been documented as a cause of CMV is well known as a systemic immunosuppressive pneumonia in a broad range of immunocompromised pa• agent, but its effects on the pathogenesis of PnCll• tients (Table 3). In the non-AIDS patient, the propensity lIlocystis remain unclear. CMV does not appear to in• for the development of Pnclilnocystis pneumonia is re• crease the morbidity or mortality due to P. carinii pneu• lated to three factors: (I) the duration of immune sup• monia in AIDS, but may increase the severity of the nression, (2) the specific drugs to which a patient has pneumonia and may require additional therapy. 75 been exposed, and (3) the naturc of the underlying dis• Recent reports of PnculIlocystis pneumonia in im• ease. 6~ The presentation of disease will vary based on munologically normal hosts have raised suspicions about the underlying predisposing condition. As a general rule, an increased environmental exposure, possibly due to P. more severe disease is seen in T-Iymphocyte deficiencies carinii in AIDS.21,76 However, these case reports lack or hematopoietic malignancies. 69 Individuals who are clear documentation of P. carinii infection and of normal malnourished or treated with corticosteroids or both tend immune function, Autopsy studies do not support the to have greater susceptibility than do patients with other existence of the organism as a commensaL However, induced immune deficiencies 70-72 The manifestations serologic studies that subclinical exposure occurs in most of disease are frequently most muted in patients receiv• individuals before the age of 5. 62,77-R 1 Various tests of ing a range of immunosuppressive agents or in AIDS immunoglobulin G (IgG) serum antibodies [immu• patients with advanced disease. nofluorescence, enzyme-linked immunosorbent assay Serologic studies suggest that seroconversion to P. (ELISA) 1 have detected infection in 1-100% of normal carinii usually occurs some time after the 3rd year of adults and in 30-100% of infected adults,77 ,80 Signifi• life. The earliest studies of Pncwnocyslis occurring in cant titers of antibody to P. carinii are detected in most the epidemic form as "interstitial plasma cell pneu• patients at the time of diagnosis of Pncwllocystis pneu• monitis" in malnourished children in orphanages dcmon• monia. 78 ,79 Detection of circulating antigen would be strate that low serum immunoglobulin and low serum preferred for establishing the presence of P. carillii. An• albumin levels are associated with both the occurrence tigen detection systems developed to date have had low and the poor outcome of this form of the disease. 10, 11.40 specificity due to impure antigen preparations used to generate the detector antibodies. Improvements in anti• TABLE 3. Conditions Associated with Pneul1locystis gen isolation (gel electrophoresis, molecular cloning) carinii Pneumonia and in antibody development (i.e., monoclonal anti• bodies) may make clinical antigen detection feasible. Acquired immunodeficiency Malignancic,. (especially hema• syndromc (AIDS) topoictic) Chemotherapy (especially corti- Congenital immune deficicncy 2.3. Acquired Immunodeficiency Syndrome costeroids) discases (ccllular. hUllloral. Radiation therapy combined) Prior to the use of prophylactic antibiotics, P. car• Organ transplantation Collagen vas':ular disease inii pneumonia was the major complication and diagnos• Prematurity Hcmatologic disorders tic manifestation of AIDS. Without prophylaxis, over Malnutrition (protein and Cushing's syndromc 80% of individuals infected with HIV would be expected caloric) Ncphrotic sY'ldrome to develop significant PncuIIJocystis pneumonia. The 282 CHAPTER 10 severity and the incidence of Pneumocystis pneumonia or emphysematous changes from prevIous infections have been reduced by the use of antiviral therapy in (Fig. 3). AIDS patients [azidothymidine (AZT), 2' ,3' -dideoxy• By the time of hospitalization, arterial hypoxemia is inosine (DDI)] and by the ability to treat simultaneous generally moderate to severe and the alveolar-arterial O2 viral infection due to CMV (ganciclovir, foscamet). The gradient is considerably widened: The degree of arterial frequency and the manifestations of Pneumocystis have hypoxemia is out of proportion to the physical and radio• also been altered by the use of prophylactic therapy. The logic findings. Dyspnea and arterial hypoxemia often beneficial effect of AZT does not seem to persist indefi• occur in the face of a normal chest radiograph. Fever is nitely. The incidence of pneumocystosis in AIDS pa• common, usually low-grade, and precedes the develop• tients is greatest with fewer than 200 CD4+ lympho• ment of respiratory symptoms. In the patient undergoing cytes/ml or in whom fewer than 20% of circulating chemotherapy, clinical manifestations of pulmonary dis• lymphocytes are CD4+ 54.69 It is likely that alveolar ease often intensify after the immunosuppressive agents macrophage activity against the organism is decreased are discontinued, and pUlmonary infiltrates appear on the by HIV infection. chest radiograph as the host's inflammatory response re• emerges (Fig. 4). Conversely, the use of corticosteroids 2.4. Clinical Pneumocystosis or cyclosporine therapy may entirely mask the signs and symptoms of Pneumocystis pneumonia until late in the The clinical manifestations of Pneumocystis pneu• course of disease. Manifestations of extrapulmonary dis• monia depend on the patient's condition: preexisting ease due to P. carinii depend on the location of infec• lung injury, immune function, concomitant infections, or tion. 83 Mass lesions of the liver or spleen may be silent. drug therapies (Table 4).61 In the adult without AIDS, P. Colonic and omental lesions have caused obstructions, carinii pneumonia is usually subacute to acute in onset, and embolid phenomena have been seen in virtually ev• developing over a few days to weeks (Fig. 3). The pa• ery organ system. tient develops progressive dyspnea, tachypnea, cyan• In the organ transplant recipient, P. carinii pneu• osis, and a nonproductive cough. Auscultatory findings monia will occur approximately 8 weeks after the initia• at the onset are minimal, generally no more than scat• tion of immunosuppressive therapy or during periods of tered rales and somewhat diminished breath sounds. In increased immunosuppression for treatment of episodes the adult with AIDS, the manifestations of the initial of organ rejection. The incidence of Pneumocystis pneu• episode of P. carinii pneumonia, usually dyspnea and monia depends on the center where transplantation is fever, evolve more slowly, often over 2-5 weeks. 29•82 performed and the immunosuppression regimens and Subsequent relapses may evolve more rapidly, especially prophylactic regimens employed there. In patients re• in the setting of other infections (e.g., CMV) or fibrosis ceiving heart-lung and single-lung transplants, the inci• dence of asymptomatic Pneumocystis isolation from TABLE 4. Clinical Presentation of Pneumocystis these organs approaches two thirds of the total number of carinii Pneumoniaa patients in some centers. Of these, approximately half

Clinical sign Non-AIDS AIDS will be expected to develop symptomatic disease in the absence of treatment or prophylaxis. By contrast, among Dyspnea Common Common other organ transplant recipients, including heart trans• Cough Common Common plants, only 5-10% will be expected to carry or develop Fever Common Common Pneumocystis infections. These patients are very in• Progression" Rapid (7-21 days) Gradual (2-5 wceks) Hypoxemia Severe Moderate to severe structive in terms of the pulmonary inflammatory re• Leukocytosis Often absent Often absent sponse to Pneumocystis infection. They tend to have a (neutropenic) (lymphopenic) lymphocyte-predominant response to the acute infection, Chest radiograph Diffuse bilateral inter- Asymmetric or bilat- with the recruitment of macrophages during and after stitial infiltrate eral interstitial infil- therapy. Despite therapy with cyclosporine, lymphocytes (much variability) trate (often normal) Response Rapid (3-5 days) Slow (5-9 days) are found in the infected transplanted lung in large num• Initial therapy bers. These are primarily T lymphocytes with normal Recurrence Unusual Common!> helper/suppressor ratios. Over half of this group of pa• Response Good Decremental; residual tients with Pneumocystis pneumonia will also have a Repeat therapy lung injury? secondary bacterial or viral infection. The heart and Side effects of Usually mild Common; some severe therapy heart-lung transplant recipients are particularly suscepti• ble to co-infection with CMY. The cytotoxic T-lympho• a Altered by type and duration of immunodeficiency. cyte-mediated response to pulmonary CMV may be diffi• hPatients taking zidovudine (AZT) or DDI may have less severe infections with delayed recurrences. cult to separate from organ rejection. The incidence of ~ a~ ~ ;;; :::! c"

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~ ~ ;I>• m =i n.... FIGURE 3. Chest radiograph of a 36-year-old man with P. carinii pneumonia following chemotherapy for a non-Hodgkin's lymphoma. A complete clinical history Z appears in Illustrative Case I (Section 2.9). Typical diffuse and bilateral, fine, interstitial infiltrates are observed. ~ nt'l >-3

oZ m

~ '" FIGURE 4. (A) Chest radiograph of a 38-year-old man with AIDS who presented with fever, cough, and malaise of 3 weeks' duration. His CD4+• lymphocyte count was 87 at the time of admission. An abscess cavity was seen in the left upper lobe. Bronchoscopic biopsy revealed only P. carinii. (B) Chest radiograph of a 43-year-old woman who became febrile and dyspneic (, weeks following liver transplantation. A small abscess cavity was seen (¢') in addition to a benign right-sided pleural effusion. Percutaneous needle aspiration of tile abscess cavity revealed P. carillii. (C) A CTscan of the chest demonstrates progression of the abscess despite therapy with intravenous pentamidine. The patient recovered completely after 4 weeks of therapy. PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 285

FIGURE 4. (Contillued) fungal infection has increased with the use of cyclo• 3).87 These infiltrates may progress to involve the entire sporine therapy, while bacterial infection has been re• lung with progressive consolidation. "Atypical features" duced. A number of centers have noted that patients with are often seen: small effusions, asymmetry or focal con• Pneumocystis pneumonia while on cyclosporine have an solidation, small nodules or cavities, linear opacities, increased mortality over other immunocompromised pa• lymphadenopathy.88-90 Distortions of the radiographic tients with Pneumocystis. pattern may occur in the presence of preexisting pulmo• Bacterial infection of the lung remains more com• nary disease (e.g., radiation or cytotoxic injury). Accen• mon than Pneumocystis pneumonia in the pediatric im• tuation may be noted in the presence of superimposed munocompromised population. 84 Early signs of pneu• viral (CMV) infection or after weaning of immunosup• mocystosis include diarrhea, poor feeding, and coryza. pressive agents (Fig. 3). Abscess formation may be due The respiratory manifestations progress to nasal flaring, to Pneumocystis alone, when P. carinii develops in a intercostal retraction, and cyanosis. Fever may be ab• preexisting cavity, or with bacterial or fungal superinfec• sent. .As in the adult, arterial hypoxemia is generally tion (Fig. 4). present along with respiratory alkalosis (pH 7.45-7.6; In the AIDS patient, radiographic disease will com• Peoz 20-40 mm Hg). Pneumocystis infection in HIV• monly progress despite appropriate therapy. While this infected children less than 1 year of age is a predictor of progression may reflect superinfection, it is more often very poor short-term survival. 84 an indication of the greater organism load seen in this patient subpopulation. The intravenous drug abuser will 2.5. Radiology of Pneumocystis carinii often have small cysts and bulli in the peripheral lung Pneumonia fields; these changes are more often perihilar with pneu• mocystosis 90 The use of aerosolized pentamidine for The variability of the clinical presentation of P. car• prophylaxis against P. carinii in AIDS patients (and in inii is matched by the radiographic picture. Like many of non-AIDS patients) has resulted in a series of otherwise the "atypical" pneumonias (pulmonary infection without unusual radiologic presentations of Pneumocystis pneu• sputum production), no diagnostic pattern exists for monia (Fig. 5). Maldistribution of drug may account for Pneumocystis pneumonia on routine chest X ray. The the development of Pneumocystis only in the upper chest radiograph may be entirely normal despite signifi• lobes . This distribution of disease, coupled with the ap• cant hypoxemia and diffuse parenchymal involve• parent tendency of these patients to develop cystic ment. 85,86 Diffuse, fine, "ground-glass" interstitial infil• changes in the parenchyma, also explains a predilection trates with a perihilar predominance are common (Fig. for spontaneous pneumothoraces. Pneumothorax may 286 CHAPTER 10

FIGURE 5. Simultaneous upper lobe infection with P. carillii and Legiollelfa pllellmophila in a 46-year-old patient with AIDS while on pro• phylaxis with aerosolized pentamidine.

also complicate the therapy of intubated patients with Alternatives to plain radiographic imaging include infection or residual fibrosis from previous Pneumocystis the computerized tomography (CT) and nuclear magnet• infection.9o The development of extrapulmonary pneu• ic resonance imaging (MRI) scans, ultrasound, and nu• mocystosis, while rarely seen in non-AIDS patients, is clear medicine imaging including gallium, radiolabeled im• probably due to the reduced systemic absorption of pen• munoglobulin, and white blood cell scans. The tissue• tamidine during aerosol administration. The clinical pre• air interface is poorly imaged by MRI and makes this sentation is generally a mass lesion of the liver or spleen. modality less useful. The CT scan often reveals diffuse In transplanted lungs, infection may be separated and nodular parenchymal involvement of the from rejection of the transplanted organ. Rejection may Pneumocystis-infected lungs in the setting of normal or cause nodular and interstitial infiltrates indistinguishable nearly normal routine chest radiographs (Fig. 6). The CT from P. carinii pneumonia. These changes are more scan is sensitive to emerging or atypical patterns of lung common in the period up to 6 weeks after transplanta• injury, including cysts and microabscesses (Figs. 4 and tion. Infection in these hosts is due to CMV more often 6). The correlation of CT scans with histopathology is than to any other single pathogen. quite good; imaging demonstrates the patchy distribution Children with epidemic "interstitial plasma cell of lung involvement and the apposition of normal par• pneumonitis" on the basis of malnutrition and crowded enchyma with consolidated tissue. Ultrasound and CT or institutional living quarters have a slowed progression scanning are both useful in the evaluation of extra• of the chest radiograph. Vascular markings and atelec• pulmonary masses due to P. carinii. This presentation tasis are more commonly seen, with hyperinflation and needs to be separated from other infections (e.g., fungi, intercostal widening preceding consolidation. In AIDS, mycobacteria) and from lymphoma or metastatic tumor. lymphocytic interstitial pneumonitis (LIP) may mimic Multiple small lesions may be seen in the liver or spleen the radiologic appearance of Pneumocystis infection. This with punctate or rim calcifications. These foci are often complication involves a diffuse lymphoid hyperplasia and better identified by ultrasound than by CT scan. They are infiltration of the interstitial space with lymphocytes. clumped hypoechoic masses that develop an echogenic PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 287

FIGURE 6. CT scan of the chest of an AIDS patient with P. carinii pneumonia and a nonnal chest radiograph. Multiple small interstitial densities and areas of parenchymal consolidation are seen. rim during therapy. Biopsy can be performed using ultra• reactions, adult respiratory distress syndrome (ARDS), sound or fluoroscopic guidance. CMV, mycobacteria, radiation injury, and other insults Each of the nuclear medicine imaging techniques is may provoke a positive image. However, the image will limited by the need for tissue inflammation to accumu• precede demonstrable infection in many patients by as late the imaging agent and to produce a localized image. much as 4-6 weeks. A negative gallium scan is rarely In marked neutropenia or uremia or in infections that do seen «7%) in pneumocystosis. Normal images should not induce much local inflammation, images may not be seen by 3-5 weeks after the start of therapy in the develop. Conversely, the diffuse inflammation that is of• absence of other processes. ten observed in the lungs of patients with AIDS (possibly Immunoglobulin scans utilize the localization of hu• due to cytotoxic lymphocytes for HIV or CMV) may man IgG to areas of capillary permeability and white cell produce false-positive images. However, nuclear medi• accumulation. The IgG scan provides a more intense cine imaging may detect inflammation earlier than other image than the gallium scan with a much lower total dose techniques. Furthermore, the ability to scan the entire of radioactivity. This sensitivity to inflammation allows body reveals unexpected findings in up to 15% of scans. the detection of focal processes (i,e., abscesses) as well Gallium citrate (67Ga scintography) scanning, ra• as the more common diffuse picture seen with P. carinii diolabeled human serum immunoglobulin ([IIIIn]-IgG) infection. This capability also allows earlier detection of imaging, 99mTc and diethylenetriamine pentacetic acid infection and the ability to follow the resolution of in• (DTPA) scans are abnormal in Pneumocystis pneu• flammation. DTPA scans are a function of fluid move• monia. 86,91-93 The diffuse uptake of 67Ga in the lungs ment and label clearance out of the alveolar space. While coupled with hypoxemia and a decreased diffusion ca• abnormal in Pneumocystis pneumonia, DTPA scans are pacity (DLco) to carbon monoxide have been used in nondiagnostic. The positron emission tomographic many centers to make a presumptive diagnosis of Pneu• (PET) scan may provide useful information about the mocystis pneumonia in AIDS patients. These tests are course of infection as metabolic labels for the growth of also abnormal in non-AIDS patients with P. carinii in• P. carinii are developed. fection. The main deficiency of this method, as with all noninvasive imaging techniques, is a lack of specificity. 2.6. Laboratory Evaluation Half the positive images seen in pulmonary gallium scans of AIDS patients will be due to P. carinii. Lymph Laboratory evaluation of the immunocompromised node uptake (AIDS-related complex) is common. Drug patient with pulmonary symptoms provides information 288 CHAPTER 10

TABLE 5. Diagnostic Techniques for Pneumocystis cariniia

Technique Yield Complications Comments

Routine sputum Poor Rare Cultures needed Induced sputum 30-55% Rare First choice; excellent in AIDS Transtracheal aspiration Fair (in AIDS only) Common: bleeding; subcuta• Rarely worthwhile neous air Gallium scan. OLeo Nonspecific Injection site Positive in >95% of infected patients Bronchoalveolar lavage >50% (>95% in AIDS) Bleeding. aspiration fever. bron• Wedged terminal BAL with im• (BAL) chospasm munofluorescence BALI brushing As for BAL alone As for BAL Not useful for P. carillii BALItransbronchial biopsy Over 90% (all patients) See BAL; pneumothorax Impression smears; cultures; pathology Open lung biopsy Over 950/, (all patients) Anesthesia. air leakage. altered "Gold standard" for noninfec• respiration. wound infection tious and infectious processes; adequate sample needed Needle aspirate Up to 60'k Pneumothorax. bleeding Best in localized disease

"All samples should be cultured and stained for bd<.:lCria (including mycobacteria). fungi, viruses, and protozoa and handled with caution. Optimal procedures will depend on the locally available expertise. about the susceptibility and the prognosis of the patient toxicity of the agents currently available for the treatment with Pneumocystis pneumonia. The level of serum lactic of Pneumocystis pneumonia in both AIDS- and non• dehydrogenase (LDH) is elevated in most patients with AIDS-infected patients, it is advantageous to have histo• Pneumocystis pneumonia [> 300 international units pathologic confirmation of the diagnosis prior to initiat• (IU)/ml]). Very high levels indicate that large amounts of ing therapy. 37 .94 In the absence of data suggesting that lung tissue are involved. and levels over 600 or 700 antibiotic-resistant organisms exist, the failure of therapy IU/ml carry a poor prognosis. Other diffuse pulmonary in the setting of known Pneumocystis infection should processes, including pulmonary emboli with infarction, suggest the presence of another simultaneous process. lymphoma, other pneumonias, and LIP, also raise serum Further, in the non-AIDS patients, no more than 15- LDH levels. The characteristic hypoxemia of Pneu• 25% of pulmonary infiltrates are caused by Pneumocys• mocystis pneumonia produces a broad alveolar-arterial tis. The broad antibacterial spectrum of trimethoprim•

P02 gradient; gradients in excess of 30 mm Hg tend to sulfamethoxazole may delay or obscure the ability to have a higher mortality. Another indicator of diffuse lung make an alternative diagnosis. Practically, in many pa• injury is an elevation in the level of angiotensin• tients, it may not be possible to make a diagnosis in• converting enzyme. This level is also increased by smok• vasively due to the patient's clinical condition. In AIDS ing and by sarcoidosis. Pulmonary function testing is not patients, the frequency of Pneumocystis pneumonia in useful diagnostically, but may indicate abnormalities in patients not receiving prophylaxis may make a therapeu• oxygen exchange. However, arterial blood gas measure• tic trial more appropriate than invasive diagnostic tests. ments are very useful in the management of patients in The optimal approach must therefore be based on the making decisions in regard to intubation and the use of patient's clinical condition. For the patient treated empir• corticosteroids as adjunctive therapy to antibiotics. Cor• ically, the physician must have a low threshold to adopt a ticosteroids have been shown to be of benefit in hasten• more invasive posture should the clinical situation dete• ing improvement in oxygenation in nonintubated patients riorate. with a Pao2 between 35 and 75 mm Hg while breathing A distinction should be made between the diagnosis room air or a "hypoxemia ratio" (Pao2 /FI02 ) between 75 of Pneumocystis infection in AIDS and in non-AIDS and 350. In the markedly neutropenic or lymphopenie patients (see Table 4).82.95.96 The burden of organisms in patient, consideration may also be given to the use of infected AIDS patients appears greater than that of the CSFs to augment the host response. otherwise immunocompromised host. Thus, the identi• fication of organisms by noninvasive techniques is more 2.7. Histopathologic Diagnosis often achieved in the AIDS patient (see Fig. 2). In gener• al, noninvasive testing should be employed to make the Identification of P. carinii as a specific etiologic initial diagnosis of Pneumocystis pneumonia, but inva• agent of pneumonia in an immunocompromised patient sive techniques should be used when necessary and clini• should lead to successful treatment (Table 5). Given the cally feasible to identify problems such as carcinoma PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 289 impinging on the airway, viral or fungal coinfection, 10% of the total infectious burden of Pncumocystis in the pulmonary embolism, or congestive heart failure. The lungs. the silver stain greatly underestimates the organ• most commonly used techniques in order of increasing ism load. To identify the presence of trophozoites, a invasiveness are outlined in Table 5. It is important to polychrome stain needs to be done, usually on impres• adapt these recommendations for the techniques avail• sion smears mad'.': from the cut surface of a lung biopsy able at a given institution and for the relative skill of the specimen or from sputum smears. These are discussed in practitioners involved in providing these diagnostic tech• some greater detail below. niques. That is, in a given institution, it may be prefer• The primacy of the interstitial injury probably ac• able to perform an open lung biopsy or needle aspiration, counts for the marked hypoxemia seen in Pncumocvstis rather than pulmonary bronchoscopy. Similarly, the yield pneumonia. While early disease is characterized by of diagnostically useful material may be greater from clumps of organisms at the alveolar epithelial surface, pathology specimens than from the clinical laboratory progressive infection causes epithelial injury and slough• that examines sputum or bronchoscopy specimens. This ing with interstitial cellular infiltration. In normal ani• judgment must be made by the physician. mals, P. carinii elicits primarily a polymorphonuclear leukocyte response in addition to alveolar macrophages 2.7.1. Histology of Infection early in disease. In the T-cell-defieient host, the inflam• matory response is muted. The nature of the infiltrate The diagnosis of P. carinii infection has been im• depends on the nature of either the underlying immune proved by the use of induced sputum samples and of defect or the immune suppressive regimen that is being immunofluorescent monoclonal antibodies to detect the used. The pathognomonic frothy alveolar infiltrate organism in clinical specimens. 61 The recognition of should be distinguished from "hyaline membranes" that small numbers of organisms in an individual without may line alveoli in oxygen toxicity, alveolar proteinosis, symptoms of pulmonary disease or without a history of or the adult respiratory distress syndrome (ARDS). All prior PCP is of uncertain diagnostic value. This is to say these conditions can coexist with Pncumocv.I'tis. In pedi• that given the presence of both cellular and serologic atric AIDS patients, LIP (see Section 2.5) may occur in exposure to Pneumocystis in the general population, it the absence of clear infectious etiology. This is a system• might be expected that Pneumocystis could be isolated in ic proliferation of lymphocytes and of lymphoid tissue, a non-immunocompromised host as either a nonpathogen but may produce the same radiologic picture as Pneu• or during a minor infection in an immunologically nor• mocystis pneumonia in this patient popUlation. In the mal host. However, therapy should be initiated with the pediatric AIDS population, bacterial infection is more isolation of this organism in an individual with altered common than is P. carinii pneumonia. immune function, especially T-lymphocyte function 69 In tissue sections or on smears, P. carinii may be Conversely, the identification of this organism in a nor• demonstrated by a variety of staining methods. Direct mal host should initiate a search for immune deficiency. immunofluorescent staining of organisms using mono• In the lungs, P. carinii produces a characteristic clonal antibodies is very useful for screening induced interstitial and alveolar infiltrate (see Fig. 2)38 This infil• sputum specimens. These antibodies generally bind both trate is diagnostic even in the absence of clearly identifia• cysts and trophozoites. The cyst wall can be displayed by ble organisms. In the malnourished infant or neonate, the a variety of staining techniques; of these, the Gomori reaction to Pncumocystis pneumonia ("epidemic pneu• methenamine-silver nitrate method (which stains organ• mocystosis") is primarily a disease of the interstitium. isms brown or black) is most reliable, even though it is The pathology of "interstitial plasma cell pneumonia" of susceptible to artifacts. Sporozoites and trophozoites are the neonate includes interstitial edema with infiltration of stained by polychrome stains, particularly the Giemsa plasma cells and lymphocytes with a characteristic frothy stain. The Giemsa, Wright's, toluidine blue 0, or Gro• exudate in the alveolar space. In the immunosuppressed cott's rapid silver stain technique is most useful in deal• adult and child, the disease tends to be more alveolar. ing with the lung imprints, bronchial lavage fluid, or The alveolar space is filled with a frothy eosinophilic pulmonary aspirates. Rapid polychrome staining (Diff• material that contains organisms and debris of macro• Quick, American Scientific Products, Inc.) and a rapid phages and alveolar epithelial cells as well as edema silver staining technique are useful in screening smears. fluid and protein. 67 The distribution of disease is often When a silver stain is used, a counterstain such as patchy, with normal lung adjacent to areas of dense con• Gram's, Wright's, Giemsa, hematoxylin, or trichrome solidation. Identification of organisms requires special may be required to identify intracystic bodies and to stains. The most commonly used tissue stain is the distinguish cysts from red blood cells and yeasts. methenamine-silver, which stains only the cyst forms of Following the resolution of acute infection, intersti• the organism (Fig. 2). Because cysts represent only 5- tial fibrosis and small areas of emphysema are often 290 CHAPTER 10 seen. The relative roles of P. carinii, drug therapy, and some experience, these commercially available kits are concomitant infection (e.g., HIV, CMV) in this pulmo• easy to use with a relatively low level of background. nary picture are unclear. In AIDS patients, residual or• The use of immunofluorescent microscopy should in• ganisms are commonly detected months after the com• crease the detection of Pneumocystis by up to 10-20% pletion of successful therapy. These organisms do not over conventional staining. The same techniques are correlate with the incidence of recurrent disease and are used to process bronchoalveolar lavage specimens. It is not thought to represent "resistant" organisms. advantageous to concentrate these specimens using a cy• Extrapulmonary disease has been reported in both tocentrifuge or a microcentrifuge prior to preparing AIDS and non-AIDS patients. Extrapulmonary organ• smears due to the effect of large fluid volumes associated isms have occasionally been identified in lymphoid tis• with bronchoalveolar lavage. sue, blood, bone marrow, liver, spleen, heart, kidney, pancreas, adrenal, thyroid, thymus, mesentery, ear, and 2.7.3. Fiberoptic Bronchoscopy eye tissue.97-100 In extrapulmonary sites, care must be taken to avoid confusing yeast forms with Pneumocystis. In experienced hands, pulmonary bronchoscopy In the AIDS patient population, dissemination is most with multiple biopsies will provide the diagnosis of often associated with prophylactic therapy with aero• Pneumocystis pneumonia in over 90% of all pa• solized pentamidine or with the absence of prophylaxis tients. 94,96,107-112 Wedged terminal lavage in aliquots of against Pneumocystis pneumonia. The patients present at least 50 cc in at least three aliquots should be sufficient with mass lesions in the liver or spleen and may develop to detect Pneumocystis infection without biopsy in over ischemic injury when clumps of organisms embolize to 80% of all patients and in up to 95% of patients with small blood vessels. These lesions must be biopsied to AIDS. The presence of other pathogens in lavage speci• distinguish them from metastatic tumor, lymphoma, or mens is often difficult to interpret. For example, the fre• focal fungal infections. quent colonization of the upper airway with Candida and the frequent isolation of CMV from such samples is of 2.7.2. Sputum Examination uncertain importance without histopathologic confirma• tion. Further, the ability to use bronchoscopic lavage for Sputum collected for routine bacterial and fungal diagnosis is completely dependent on the skill of the stains and cultures is rarely usable for the diagnosis of laboratories handling the specimens. Biopsies are not Pneumocystis pneumonia. 37 ,101 The technique of sputum generally needed to make the diagnosis of P. carinii induction has been very useful in the diagnosis of Pneu• pneumonia in AIDS, but will often provide useful infor• mocystis infection in all immunocompromised individu• mation about the patient's status in regard to interstitial als when coupled with the use of immunofluorescent injury after chemo- or radiotherapy, viral infection, antibodies for the detection of Pneumocystis in these ARDS, or response to therapy. The complication rate is specimens. 95, lD2-106 Sputum induction has become the institution-dependent, but generally low. Biopsies (open diagnostic technique of choice for P. carinii. It should be or bronchoscopic) may be preferred if the clinicallabora• noted that many bacteria will not grow after exposure to tories lack experience with P. carinii. hypertonic saline, so it is important that routine sputum collection be utilized for bacterial and fungal diagnosis. 2.7.4. Transtracheal Aspiration and Percutaneous Patients are exposed to aerosolized hypertonic saline or Needle Aspiration water for up to 30 min, and smears are prepared from the mucoid portion of the collected specimens. Smears can Transtracheal aspiration for the diagnosis of Pneu• be prepared in a number of ways, including after treat• mocystis infection is to be avoided. The incidence of ment of the specimen with a mucolytic agent (acetylcys• complications outweighs the potential benefit of the rap• teine, Mucomyst) or dithiothreitol just prior to making id production of a diagnostic specimen. Given the advan• the smear. The cytocentrifuge has also been very useful tages of immunofluorescent staining coupled to induced for this purpose. Smears should be stained with Giemsa sputum or bronchoscopy, the inexperienced practitioner or Diff-Quik stains for the intercystic bodies or with should avoid transtracheal aspiration. In experienced toluidine blue 0 or rapid silver stain, which stain the cyst hands, the diagnostic yield of tracheal aspiration is lower wall (Fig. 2). Because cyst stains detect only 5-10% of than that achieved by induced-sputum examination when the total organisms, the Giemsa stain is preferred over both are coupled to immunofluorescent microscopy. the more complex silver stain. However, the Giemsa Radiologically guided percutaneous needle aspira• stains are difficult to read. This problem has been over• tion of the lung produces diagnostic specimens in up to come by the use of monoclonal antibodies directed 60% of patients with P. carinii pneumonia. 113 This tech• against surface epitopes from P. carinii. lOl.104 With nique is useful both in diffuse lung disease and in the PNEUMOCYSTIS CARlNII AND PARASITIC INFECTIONS 291

TABLE 6. Treatment of Pneumocystis carinii infections a

Agent(s) (route)h Dose Optionsh

Trimethoprim 15 mg/kg/day TMP (to 20 mg) Treat through rash: Reduce TMP or SMZ And sulfamethoxazolc (IV/PO) 75 mg/kg/day SMZ (to 100 mg) by one half; desensitize

Pentamidine isethionate (IV) 4 mg/kg/day; 300 mg/day maximum Lower dose (2-3 mg/kg); 1M route not advised

Dapsone (PO) 100 mg/day Methemoglobinemia; G6PD; may be toler• With TMP (PO/IV) 15-20 mg/kg/ day (900 mg) ated in sulfadiazine allergy

Clindamycin (IV/PO) 600-900 mg q6h Methemoglobinemia; diarrhea And primaquine 15-30 mg base qd

Trimetrexate (IV) 30-45 mg/m2/day Leukopenia, anemia; thrombocytopenia; With folinic acid (leucovorin) 80- 100 mg/m2/day relapse common

Pyrimethamine Load 50 mg bid x 2 days, Not studied fully then 25-50 mg qd With sulfadiazine Load 75 mg/kg, then 100 mg/kg/day Maximum 4 g in two doses; up to 8 g

Piritrexim Under study Like trimetrexate With folinic acid

566C80 (investigational) Under study (750 mg bid-qid, PO) Variable absorbance, better with food; rash

Prophylaxis (after P. carinii pneumonia or with <20% CD4+ lymphocytes/ml or <20% CD4+ lymphocytes or with rapid disease progression): AZT or DDI; aerosolized or intravenous pentamidine (up to 300 mg q3-4 weeks); TMP-SMZ (160 mg TMP, PO bid/qd or 3 days/week); dapsone (100 mg/day; rule out G6PD, methemoglobinemia); Fansidar (I tab qwk; rule out hepatitis, erythema multiforme). uAdjuflctive therapies (see Section 2.8.4): corticosteroids (high-dose with rapid taper); intcrferon--y: macrophage colony-stimulating factor; aerosolized pentamidine. bBased on the physician's clinical judgment; some agents arc not FDA-approved for this indication. evaluation of focal and peripheral processes seen on has increased. 25 ,115 For most of the available antibiotics, chest radiograph or CT scan. Pneumothorax is common the potential for side effects such as rash, hepatitis or (up to a third of cases in some series); 20% of pneu• pancreatitis, or GI intolerance must be balanced against mothoraces require chest-tube insertion. Inadequate the potential for bone marrow suppression, which is specimens and bleeding are the other main complications common to almost all the agents discussed in this section of this technique. and in Table 6. 116 A few general points may be made about therapy: 2.7.5. Open Lung Biopsy 1. The most effective systemic therapy for the treat• ment of P. carinii pneumonia in all patients remains Surgical open lung biopsy remains the "gold stan• trimethoprim-sulfamethoxazole (cotrimoxazole, TMP• dard" for the evaluation of pulmonary processes in the SMZ).I17-120 This consideration includes such factors as immunocompromised host.11 4 When the procedure is the onset of action and ease of administration (availabili• performed by skilled surgeons, the complication rate of ty in all forms). thoracotomy and biopsy should be low. This approach 2. The use of adjunctive therapies (colony• provides the best specimen for cultures and histopathol• stimulating factors, immune modulators, aerosolized ogy. The sampling of a larger segment of the lung may pentamidine, corticosteroids, antibodies) must be tai• assist in clinical decision-making. The presence of CMV lored to the individual patient. in alveolar cells is useful data; culturing CMV from lav• 3. Experience in AIDS patients suggests that treat• age fluid is nondiagnostic. Impression smears taken from ment can be continued through the occurrence of mild the cut surface of the lung biopsy are often adequate for side effects including rash, mild elevation of serum liver the diagnosis and treatment of P. carinii pneumonia. function tests, and slight bone marrow depression. Such treatment may require adjustments in dosage, the inter• 2.8. Therapy of Pneumocystis carinii Infections val of administration, or the form of the antibiotic given. These guidelines are not universally applicable to non• Due to the frequency of P. carinii pneumonia in AIDS patients, in part because the incidence of adverse patients with AIDS, the number of therapeutic options reaction in this popUlation is much lower. available for the treatment of Pneumocystis pneumonia 4. Pneumocystis carinii that is resistant to antibiot .. 292 CHAPTER 10 ics has not yet been demonstrated. The apparent failure available and requires different dosing than the isethio• of an individual patient to respond to therapy may ieftect nate form available in the United States. Pentamidine is a either inadequate serum or tissue levels of antibiotic or very useful drug in the treatment of AIDS patients aller• greater lung injury. Switching agents for reasons other gic to cotrimoxazole, but is probably a drug of second than toxicity is not recommended.116.120.121 Of interest choice in the non-AIDS patients who tolerate TMP• is the observation of a reduction in the incidence of anti• SMZ. biotic side effects in groups treated with corticosteroids The incidence of side effects to intravenously ad• as an adjunct to antibiotic therapy. ministered pentamidine is roughly equivalent to that seen 5. Coinfection with pathogens in addition to P. with cotrimoxazole in AIDS patients. 120 Adverse reac• carinii is common. tions are both idiosyncratic and dose-related. Adminis• 6. The duration of therapy in the immunocompro• tration of pentamidine in the presence of renal dysfunc• mised patient with Pneumocystis has not been studied tion is associated with an increased incidence of most of carefully. The choice of 14-day courses of therapy in the side effects of pentamidine therapy. These adverse non-AIDS patients and of 21-day courses of therapy in reactions include hypoglycemia, hyperglycemia, neu• AIDS patients is largely arbitrary. Shorter courses may tropenia, thrombocytopenia, azotemia. pancreatitis, nau• well be effective, especially in the setting of antibiotics sea, and altered taste sensation. Pancreatic dysfunction is with long serum half-lives. In patients with persistent more common after a total dose exceeding 3 g pentam• immune deficiency, prophylaxis should be considered. idine. This injury may occur after the cessation of thera• Residual organisms present in bronchoalveolar lavage py because of the prolonged half-life of the drug, which specimens at the completion of therapy are of uncertain is frequently over 2 months. Hypoglycemia or hyper• importance, but are largely nonviable. These organisms glycemia may precede permanent insulin dependence. do not correlate with the incidence of recurrent disease. Despite initial enthusiasm, aerosolized pcntamidine has Non-AIDS patients respond to therapy and prophylaxis not proven useful for the initial therapy of Pneumocystis as well as or better than patients with AIDS, and with pneumonia, but may be useful as an adjunct to therapy. fewer adverse reactions. A hepatic metabolite of pentamidine may be responsible for most of the toxicities of this agent. New diamidines 2.8.1. Pentamidine with fewer side effects and greater efficacies are under development. Pentamidine isethionate was the first agent em• ployed for the successful therapy of P. carinii pneu• 2.8.2. Trimethoprim-Sulfamethoxazole (TMP• monia. 10.40.117.122.123 Pentamidine was first adminis• SMZ, Cotrimoxazole) tered intramuscularly in an epidemic of infantile Pneumocystis pneumonia. In this population, it reduced Trimethoprim-sulfamethoxazole (Bactrim, Septra) mortality from 50% to 3.5%. The success of pentam• is thc drug of first choice for the treatment of P. carinii idine therapy in subsequent trials varied widely, with pneumonia in patients who tolerate this agent. 24.26. survival rates of 25-85% of affected individuals. While 118-120.124-127 This preference is based on (1) the avail• pentamidine therapy is generally successful in up to 75% ability of both intravenous and oral formulations of the of individuals, over half will have adverse effects when drug, which enhances the ease of administration; (2) the receiving this drug via the intramuscular route, the major ability to follow serum levels of the sulfa component; complications being sterile abscesses at the site of injec• and (3) the efficacy of this drug for both therapy and tion. Currently, pentamidine isethionate is given intra• prophylaxis. The onset of action for cotrimoxazole is venously by infusion over 1-2 hr in a 5% glucose solu• rapid; clinical responses are seen as early as 3 days into tion at a dose between 2 and 4 mg/kg per day. Because of therapy. Serum levels with orally administered drug are the prolonged half-life of this drug and the high levels of equivalent to intravenous levels, given normal Gl func• tissue binding, it may be advantagcous to bcgin therapy tion. Therapy is generally initiated with a total dose of 20 at the 4 mg/kg per day level and to use lower doses mg/kg per day of TMP coupled with 100 mg/kg per day subsequently. Therapeutic efficacy is achieved more of SMZ divided into 4 daily doses. Peak serum levels are slowly than with other agents, often requiring 5-7 days reached within 2 hr after oral administration and proba• before clinical improvement is observed. Therapeutic bly in thc range of 5-15 f,lg/ml of TMP and 100-150 levels persist in the lungs long after treatment is com• f,lg/ml of SMZ. Serum SMZ levels of over 200 f,lg/ml pleted. Pentamidine may playa role in the reduction of are associated with a somewhat higher incidence of drug symptoms duc to reduced secretion of tumor necrosis toxicity. in particular bone marrow suppression. The rap• factor by macrophages involved in the phagocytosis of P. id onset of action of this agent may provide the margin carinii. In Europe, pcntamidine methanesulfonate is also necessary to avoid intubation of thc critically ill patient. PNEUMOCYSTIS CARINlJ AND PARASITIC INFECTIONS 293

In the non-AIDS patient, TMP-SMZ evokes many fewer has been effective. 128-131 Dapsone has been tolerated in adverse reactions than does pentamidine. The rates of many patients with proven sulfa-drug allergy. Particular adverse reactions in the AIDS patient population are caution must be exercised when using dapsone in this roughly equivalent and amount to 50% of all patients patient group, however, because hypersensitivity may who take either agent. A course of 14 days of therapy is cross between sulfa- and sulfone-containing drugs, and adequate if immune suppression can be reduced or re• dapsone has a prolonged half-life, which makes side ef• versed; 21 days of therapy is preferred in AIDS patients fects not rapidly reversible. The absorption of dapsone or patients on chronic immune suppression (organ trans• from the GI tract may be reduced by antiviral therapy plant recipients) in whom immune suppression cannot be with DDI (2' ,3'-dideoxyinosine, Videx).132 Preliminary varied. Chronic immune suppression requires prophylac• data supporting a number of other combinations have tic antibiotic therapy in patients who have had an episode also been accumulated. Clindamycin-primaquine and of Pneumocystis pneumonia. pyrimethamine-sulfadiazine have been useful both in the The proper dosing of TMP-SMZ in adults has not animal model and in human trials. 133-136 Clindamycin been studied.121.125 The dosing regimens in common use given intravenously (600-900 mg IV qSh for 10 days) is were developed in children with leukemia and have not slightly more effective than oral administration (600 mg been reevaluated in adults with any form of underlying PO q6-Sh) for mild to moderately severe Pneumocystis immune deficiency. While successful, these levels may pneumonia. Clindamycin is given with oral primaquine be excessive, and it is worth monitoring serum levels at (15-30 mg EPO base per day), with the major toxicities some point during the course of hospitalization. In the being gastrointestinal. The macrolides (erythromycin, immunocompromised host, TMP-SMZ covers a broad clarithromycin, or azithromycin) coupled with SMZ spectrum of organisms, including Listeria, Nocardia, have also proven useful in animal models and in small and many of the common bacterial pathogens including groups of patients. The erythromycin and sulfa combina• both encapsulated and unencapsulated gram-negative tion is of particular interest because of the broad spec• and gram-positive organisms. Thus, there may be unex• trum of coverage available in the immunocompromised pected beneficial effects when treating a patient for host and because of the long history of use of this combi• Pneumocystis with this agent. nation in pediatric infectious disease patients. Of inter• The toxic side effects of TMP-SMZ are generally est, few of these agents have much activity on their own those of sulfa allergy. In the AIDS patient population, the against P. carinii. Synergism between these agents can adverse reactions to this drug include reactions to TMP be demonstrated in animal models. The optimal dosing and to the carriers and dyes present in various formula• of these combinations has not been established for the tions. Some of the allergies in AIDS patients can be quite treatment of Pneumocystis pneumonia. Some recom• severe, including Stevens-Johnson's syndrome, hepato• mendations are presented in Table 6. toxicity with eosinophilia and cell necrosis, erythema Further alternative regimens include trimetrexate, a multi forme exudativum, and nephrotoxicity. Both com• dihydrofolate reductase (DHFR) inhibitor originally de• ponents in the combination can produce bone marrow veloped as a chemotherapeutic agent for cancer pa• suppression, including thrombocytopenia and neutro• tients. 137- 139 This drug has high affinity for isolated penia; these side effects arc frequently reversible by re• DHFR from Pneumocystis as compared to human ducing the total dose of the drug or supplementing with DHFR, but is consistently toxic to the bone marrow, folinic acid. The bone marrow suppressive effects are great• requiring folinic acid (leucovorin) to allow administra• er in patients with underlying hematologic disorders or tion. This combination is expensive and remains investi• those receiving cytotoxic chemotherapy. Folinic acid should gational. Trimetrexate has the unique advantage of being probably not be used in patients with acute leukemias. lipid-soluble with a long serum half-life of up to 34 hr. 140 Side effects (fever, rash, leukopenia, liver function test 2.8.3. Alternative Regimens abnormalities) occur in over a third of patients, and re• currence of Pneumocvstis is very common. Another Multiple new drugs and drug combinations have lipid-soluble DHFR inhibitor, piritrexim, coupled with been used in the treatment of Pnewnoc\,stis since the sulfonamide also appears useful, and a variety of newer onset of the AIDS epidemic. Because of the frequency of inhibitors (BW 566CSO) are under study. 141 Atovaquone adverse reactions in AIDS patients, most of these regi• (Mepron, Burroughs-Wellcome, 566CSO) has been ap• mens have been used almost exclusively in the sub• proved for the treatment of mild-to-moderate infections. population of AIDS patients with allergies both to TMP• DFMO (a:-difluoromethylornithine, Merrell Dow) has SMZ and to pentamidine. The combination of TMP (at been used to treat Pneulflocystis pneumonia in some pa• 20 mg/kg per day in 4 doses) and dapsone (4'4'• tients with AIDS who do not respond or who are intolerant diaminodiphenyl sulfone, Jacobus, 100 mg orally/day) of other regimens. 142 Most of the patients successfully 294 CHAPTER 10 treated with this regimen had completed some course of ing disease due to HIV was not observed. Patients did therapy with pentamidine. The prolonged half-life of this observe an increased incidence of oral herpes simplex latter agent may count for those early successes. Subse• with oral thrush, both of which are improved with care• quent experience has been more disappointing. ful attention to oral care. An alternative approach to the suppression of the 2.8.4. Adjunctive Therapies acute inflammatory response is the augmentation of the immune response to Pneumocystis using immune mod• Many patients with P. carinii pneumonia will suffer ulators. 58 Animal studies and some clinical anecdotes disease progression despite appropriate antibiotic thera• have suggested that interferon-"{ (IFN-"{) has the effect of py. Especially prone to do so are debilitated patients or reducing the amount of Pneumocystis found in infected those with marginal oxygenation. In this setting, the ini• lungs, probably by enhancement of the macrophage re• tial delay of 4-·7 days before responding to therapy may sponse. IFN-"{ administered either intravenously or by necessitate intubation with mechanical ventilation. It aerosol may accelerate the clearance of organisms with• may well be that the successful killing of intra-alveolar out greatly enhancing the local inflammatory re• organisms may contribute to the local inflammatory pro• sponse. 57 .58 In leukopenic patients or in AIDS, an alter• cess and further diminish oxygenation. These patients native would be the utilization of macrophage or will often require supplemental oxygen and are at risk for granulocyte-macrophage colony-stimulating factors (M• bacterial and fungal superinfection after intubation. One CSF or GM-CSF). Unlike the effect of IFN-"{, the effects approach to this problem has been the judicious use of of CSFs on local immunity may require T-lymphocyte corticosteroids in selected patients with Pneumocystis function. There is controversy regarding the use of CSFs pneumonia with hypoxemia and prior to intubation early in patients infected with HIV due to increased viral repli• in the patient's course. Recent clinical trials have demon• cation in the presence of M-CSF and GM-CSF. It is not strated that corticosteroids administered in the first 72 hr yet clear whether or not these effects are of physiologic of therapy for Pneumocystis pneumonia are of significant significance. benefit in AIDS patients in terms of morbidity, mortality, The role of aerosolized pentamidine remains un• and the avoidance of intubation in patients with an arte• clear in the acute management of patients with Pneu• rial P02 on room air between 35 and 72 mm Hg or with a mocystis pneumonia. The distinct advantage of having an hypoxemia ratio (Pa2/FI02) between 75 and 350.143-146 agent that does not disseminate systemically and obtains Experience with both neutropenic and organ transplant high local concentrations appears obvious. It may be that patients with Pneumocystis pneumonia has been equally aerosolization of pentamidine is a useful supplement to gratifying. In AIDS patients, the benefits of early steroid intravenous pentamidine therapy in the first few days therapy were as follows: up to a 50% reduction in pa• prior to obtaining good lung tissue levels of this agent. tients requiring intubation, a marked reduction in the Other immune modulators are being evaluated for the number of patients experiencing deterioration in oxy• treatment of Pneumocystis. Preliminary data suggest that genation during the first 7 days of therapy, a reduction in some of the newer antibiotic agents (e.g., the echinocan• the number of side effects due to antibiotics observed, a dins or quinolones) will also be useful. significant decrease in patient mortality in the first 84 days after hospitalization (to 50%), and a persistent im• 2.8.5. Response to Therapy provement in exercise tolerance after the completion of therapy. In addition, many of these patients were found The manifestations of Pneumocystis pneumonia to eat better. Patients with undiagnosed CMV adrenalitis have changed both because of new prophylactic antibiot• may also benefit. The incidence of side effects was sur• ic therapies and because of new immunosuppressive reg• prisingly low when the patient was given a maximum of imens, including those with cyclosporine. The response 14 days of tapering steroid therapy. Patients in whom to therapy has also changed with these new regimens. steroid therapy is not tapered are prone to recrudescence AIDS patients are presenting with advanced disease and of hypoxemia and of acute pulmonary symptoms. The with atypical manifestations (upper lobe disease, multi• optimal dose of steroids has not been established. One ple infections, extrapulmonary disease) or with a history useful regimen is a dose of 40-60 mg prednisone or of adverse reactions to one or another of the primary prednisolone given orally or intravenously twice a day. therapeutic agents. In general, the non-AIDS immu• After 5-7 days, the steroids are tapered over a period of nosuppressed patient does better with initial therapy for 7 days to 2 weeks. Predictable side effects of steroid P. carinii pneumonia than does the AIDS patient. The excess are rarely seen with a short course of modest response is more rapid, and recurrence is relatively un• steroid doses. An excess incidence of opportunistic in• common. Failure of a patient to respond to cotrimox• fection, gastric irritation, or acceleration of the underly- azole therapy in 5-7 days is unusual. However, little PNEUMOCYSTIS CARlNll AND PARASITIC INFECTIONS 295 benefit is likely to be seen if a switch to pentamidine is moxazole were the prevention of infection due to Pneu• made before 7 days into the course of therapy. The chest mocystis as well as toxoplasmosis, Listeria, Nocardia, radiograph may progress while oxygenation and non• and other bacterial pathogens. The incidence of side ef• specific indicators of lung injury gradually improve. fects was fairly modest with relatively short periods of Failure to improve is more often due to other factors than prophylaxis. In the non-AIDS patient, prophylactic ther• it is to failure of a given antibiotic. Adding pentamidine apy should be reserved for patient populations known to to TMP-SMZ offers no advantage over simply switching have a predictably high incidence of Pneumocystis infec• agents, and there may be antagonism between these tion or those who have had recurrent opportunistic infec• agents when used in -combination. Patients switched tions or Pneumocystis infections in the past. Oral admin• from cotrimoxazole to pentamidine for reasons of thera• istration of 5 mg/kg per day of TMP as cotrimoxazole peutic failure generally do less well than patients who are divided into two daily doses or 150 mg/m2 per day suc• able to be treated for 2-3,weeks on either agent. Of the cessfully prevents the development of Pneumocystis in• newer agents, there appears to be antagonism in the ani• fection. Even on this modest dosage, bone marrow sup• mal model between erythromycin and 566C80. Antibiot• pression is relatively common, but usually mild. It is ic resistance has not been demonstrated in P. carillii. equally effective to administer cotrimoxazole 3 days However, this may reflect the limitations of the in vitro each week (either consecutive or alternative) with one culture system. The clinical assessment of the patient is double-strength tablet at bedtime. Lower doses of antibi• usually the best guide to subsequent therapy. Patients otic have also been effective. 147 These doses of drug are who fail to respond to antibiotics within 7 days or so are usually well tolerated, with minimal incidence of side good candidates for bronchoscopy with biopsy or lavage effects and relatively modest bone marrow suppression. or both to clarify the nature of their progressive pulmo• Alternative regimens are occasionally necessary in non• nary disease. AIDS patients requiring prophylaxis. These patients will The survival of patients on anti-Plleumocystis thera• tolerate pentamidine 300 mg by aerosol or intravenously py has improved to between 80% and 90% at most medi• every 3-4 weeks. In these patients, dapsone (100 mg cal centers. AIDS patients receiving zidovudine (AZT) orally a day) is also effective, as is weekly Fansidar have fewer and less severe episodes of Pneumocystis (pyrimethamine-sulfadoxine).149 The use of these latter pneumonia. However, of patients developing opportunis• two agents should be guided by knowledge of their side tic infections, the fraction with Plleumocystis remains effects (see below). about the same, at 50-60%. The benefits of AZT therapy In AIDS patients, prophylaxis against P. carillii is appear to diminish somewhat over time. Patients on pro• critical. The incidence of Plleumocystis is greatest in phylactic antibiotics may avoid recurrence of P. carillii patients with less than 200 CD4+ lymphocytes/ml blood pneumonia. Complications of therapy are more common or less than 20% CD4+ lymphocytes total. While these in the AIDS population, including a to-fold increase in guidelines are useful, the incidence of Plleumocystis the incidence of significant skin rash and fever. Hepatic pneumonia is also very high in patients with rapidly pro• toxicity occurs in up to 20% of these patients. Minor gressive immune deterioration, or a prior history of adverse reactions (skin rash or transient liver function Plleumocystis infection, or both. Recent evidence sug• test abnormalities) may be due to either component, and gests that while aerosolized pentamidine is still very pop• these are often reversed by continuing the drug at the ular, it has been less successful in preventing Plleu• initial or reduced levels. It is worth checking serum SMZ mocystis infection than has TMP-SMZ. TMP-SMZ is levels if side effects occur. Serious toxicity requires now the agent of choice in patients who tolerate it for the switching to an alternative regimen. prevention of Pneumocystis infection. 150, 15 I Lower-dose regimens of TMP-SMZ are generally well tolerated (in 2.9. Prevention of Pneumocystis carinii up to 75-80% of AIDS patients); potential side effects Pneumonia in the Susceptible Host are those seen in therapy. In patients completing therapy with cotrimoxazole, prophylactic therapy should be initi• Pioneering studies in children with hematopoietic ated immediately to prevent sensitization to this agent. malignancies, especially those on corticosteroid therapy, In patients who do not tolerate cotrimoxazole, pen• led to the development of TMP-SMZ for the prevention tamidine aerosol has been very useful. This mode of of Pneumocystis pneumonia. 71 ,72,119.124.147,148 The suc• drug administration has been associated with atypical cessful experience with prophylaxis at the Saint Jude's presentations of Plleumocystis pneumonia, including ex• Children's Research Hospital was broadened to include trapulmonary Plleumocystis infection and pneumotho• immunocompromised adults and in patients with severe races in some patients. Successful administration of combined immunodeficiency syndrome (SCID) at risk aerosolized pentamidine depends not only on the dosage for Pneumocystis infection. 147 The advantages of cotri- and schedule of administration, but also on the nebulizer 296 CHAPTER 10 used to create the aerosol. It has been found that health presented with fevers. a diffuse pulmonary process. and hypoxemia. care personnel may be exposed to both pentamidine and His chest X ray [Fig. 3 (Section 2.4)1 had both alveolar and interstitial infectious agents in the lungs of AIDS patients during the infiltrates at the time of transfer from an outside hospital. The patient has been followed for a stage 1 high-grade B-celllymphoma diagnosed course of nebulization. The nebulizer must produce a 2 years prior to admission. The pathology on this tumor included cells mist of 1-3 f.Lm droplets to be successful. Careful posi• varying from small noncleaved. non-Burkitt's cells to immunoblasts. tioning of the patient assists in the proper distribution of He was initially irradiated in the left groin area. but had a recurrence in this drug. A tightly closed nebulizer system and dedi• the right groin 1 year later with the same histology. At the time. his catcd room must be considered for the safe administra• abdominal CT and bone marrow biopsy did not reveal tumor. and he started trcatment with ProMACE-cyta-BOM: multiple courses of cyt• tion of this agent to AIDS patients. Patients who are oxan. adriamycin. and VP 16. followed by bleomycin. vincristine, intolerant of aerosolized pentamidine may benefit from methotrexate. and cytosine arabinoside, followed by high-dose pred• the use of bronchodilators prior to administration or may nisone. He had completed four cycles of therapy and was on high-dose be treated intravenously. The side effects of pentamidine prednisone at the time of his admission to the Massachusetts General will develop more slowly in the aerosolized treatment Hospital. His presentation followed the development of diffuse bilat• eral pulmonary infiltrates over a period of 4 days. He had been treated group, but can still be expected to occur in patients after with oral amoxicillin-c1avulanate. He developed a rapid deterioration a total dose of 3 g. Aerosolized pentamidine also has the of pulmonary function. He was markedly hypoxemic, with diffuse rales effect of reducing the number of organisms such that and rhonchi. fever to 1OlaF. with a total white blood count of 2000 diagnosis of recurrent or of upper lobe disease is occa• (42'7<, polymorphonuclear leukocytes). sionally delayed based on induced sputum examination. After transfer, initial antibiotic coverage was broad; his antibiotics included cotrimoxazole (TMP-SMZ) for the presumed diagnosis of However. this agent has proven very useful in large pop• Pnellmoc,vSlis carinii pneumonia as well as erythromycin, ticarcillin. ulation studies. gentamicin, and vancomycin. Induced sputum was noted to contain P. Some of the longer-acting sulfa-derived agents in• carillii by direct immunofluorescence. Initial blood, urine, and sputum cluding Fansidar and dapsone have been useful in pre• cultures were negative for other pathogens, including CMY. When first seen in consultation, he had completed approximately venting infection at relatively low cost. 14~-152 Break• 14 days of pentamidine isethionate after 7 days of TMP-SMZ and through infections have been seen with dapsone at 50 was on a gradual steroid taper. His course had been complicated by a mg/day doses, and side effects are more common at the skin rash and fever. prohably due to TMP-SMZ, and thrombocytopenia recommended 100 mg/day dose. This drug is occasion• due to pentamidine. Notable in his course was that despite therapy ally associated with nausea, asymptomatic methemoglo• for Pllellmocvsris for 21 days. his chest radiograph had failed to im• binemia, and hemolytic anemia, especially in glucose-6- prove, with diffuse infiltrates consistent with adult respiratory dis• tress syndrome. The effects of past chemotherapy were also con• phosphate dehydrogenase (G6PD)-deficient patients. sidered. There is some suggestion that DDI use in the treatment of It was recommended that the patient be taken for open lung biopsy HIV infection may interfere with the absorption of dap• due to the failure of his chest X ray and pulmonary functions to im• sone from the GI tract. Fansidar administered weekly has prove, and the inability to isolate further pathogens. At the same time, also been effective in clinical trials. Conccrns about this his anti-Pneul11ocvslis therapy was stopped (other than prophylactic pentamidine, 300 mg intravenously every 3 weeks). The lung specimen agent are derived from its long half-life and the occasional grew CMV overnight via Shell vial. Pathology demonstrated an inter• episode of severe hepatitis in some individuals taking stitial process consistent with lung toxicity due to cytoxan in addition to Fansidar for prophylaxis against malaria. Atovaquone the CMV infection and rare P. carillii cysts. On the basis of these may also be useful for prevention of Pneumocystis infec• results. he was treated with ganciclovir (DHPG), at an initial dose of tion, especially in patients intolerant of sulfa drugs. 450 mg intravenously every 1:2 hr. His steroid taper was continued. Despite some early radiologic improvements with lysis of his fevers, Concerns about the prevention of Pneumocystis the chest X ray failed to improve greatly: however. his oxygenation have also led to considerations about the possible person• improved markedly during therapy. He completed 21 days of antiviral to-person spread of this organism. While serologic stud• therapy and was discharged home. He has received ganciclovir and ies have suggested that such transmission is possible, the dapsone prophylaxis for subsequent periods of chemotherapy. Bacterial strongest suggestion of person-to-person transmission is and fungal cultures remain negative. Commenls. This case illustrates the complexity of the manage• the increased incidence of Pneumocvstis pneumonia in ment of immunocompromised patients with the "febrile pneumonitis non-AIDS patients in institutions caring for AIDS pa• syndrome." The likelihood of significant infection rises with the tients with Pneumocvstis infection. Patients infected amount and the duration of immune suppression. The rapid progression with Pnellmocystis should not share rooms with other of P. carinii is typical for this infection in a non-AIDS patient. The immunocompromised patients. This problem merits frequency of side effects of therapy for P. carinii is illustrated by the leUkopenia (due to cotrimoxazole) and thrombocytopenia (due to pen• study and may benefit from the ability to do epidemio• tamidine) seen in this host. Initial management with oral amoxicillin• logical chromosomal mapping of P. carinii isolates. c1avulanate in a sick. compromised patient and in the absence of micro• biologic (Gram's stain) evidence for bacterial infection is worrisome. Illustrative Case 1 Delays in the recognition and treatment of Pneumoc,vslis pneumonia contrihuted to this patient's progressive deterioration. The use of corti• The patient i, a 36-year-old man with a non-Hodgkin's lymphoma costeroid, in chemotherapy proved to be a microbiologic double-edged treated with high-dose corticmteroids and cytotoxic chemothcrapy who sword. Steroid therapy is probably the main factor in the devclop- PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 297 ment of infection in this host. but may decrease pulmonary inflam· by infection with T. gOlldii. The presence or absence of mation and transiently improve oxygenation in the acute setting. While the organism in tissues ("infection") is not indicative of well studied in AIDS patients. steroid therapy for P. carinii pneu• clinical disease ("toxoplasmosis") in the absence of the monia has not been examined in the heterogeneous non-AIDS popula• appropriate clinical presentation. Acute infection in the tion. Failure to improve pulmonary function by day 7-10 of therapy for immunocompromised individual requires prompt diag• P. carinii infection should suggest additional evaluations. Congestive nosis and therapy to avoid significant injury. The impor• heart failure. pulmonary embolus, and bacterial superinfection [Fig. 5 tant role of infection of the central nervous system (CNS) (Section 2.5)] are common cofactors. Because antibiotic resistance has by this organism complicates both the diagnosis and not yet been demonstrated in P. carinii, switching therapy for reasons other than toxicity is not recommended. An aggressive approach to the treatment of toxoplasmosis. This problem is further histopathologic diagnosis is ajien required in the absence of a reason• compounded by the lack of reliable and reproducible able microbiologic diagnosis. The ability of the patient to tolerate serologic tests for use in immunocompromised individ• invasive procedures is best earlier in the course of illness. In this uals. patient. the successful treatment of P. carinii pneumonia was masked Since its description in the gondii, a rodent from by CMV pneumonitis and by pulmonary toxicity due to chemotherapy. Treatment of CMV pneumonia with ganciclovir (not an FDA-approved North Africa, and in rabbits, it has become apparent that indication) produced a rapid clinical improvement. The likelihood of there are strain differences among T. gondii isolates from recrudescence of infection due to P. carinii or CMV or both necessi• various regions of the world.153.154 tates prophylaxis for subsequent periods of neutropenia and corticoste• roid therapy. 3.1. The Organism

3.1.1. Life Cycle 3. Toxoplasma gondii Toxoplasma gondii is an obligate intracellular proto• Serologic evidence suggests that up to 70% of all zoan of the order Coccidia. The multiple developmental individuals are exposed to Toxoplasma gondii at some stages of T. gondii are relevant to the clinical manifesta• point during their lives. Thus, it should be considered tions of toxoplasmosis (Fig. 7). Oocysts initiate the life surprising that Toxoplasma causes significant infection cycle of T. gondii and are produced only in the intestines only infrequently outside the immunocompromised host. of members of the cat family. This form of organism is In immunocompromised adults and in fetuses, this rela• oval in shape, measuring 10-15 f.Lm in diameter, and is tively benign organism causes significant morbidity. produced in the small intestine following both asexual Toxoplasmosis represents a spectrum of diseases caused (schizogeny) and sexual (gametogeny) reproduction.

J\~ ' · EnTeroeplTheliol Cycle '.1~ MOUSEi:1- DEFINITIVE HOST RAT' CAT Oocysts (Feces) ( ~ ExtromTestlnal Cycle Tissues' Under cooked TrophOZOI Tes Food or Cysts in Food ------~. MAN TransfuSIOn OTHER ANIMALS ~ Orgon Transplant INTERMEDIATE, HOSTS ~:::,on\mro / Acute

Congen,tol Chranic DisseminaTed

FIGURE 7. Life cycle of Toxoplasma I{ondii. 298 CHAPTER 10

Self-propagating infection (the enteroepithelial cycle) tions of Toxoplasma that vary in virulence and may have within the intestinal epithelium generates millions of 00- differing developmental characteristics, including a pre• cysts per day in cat feces. Fecal oocysts will survive for dilection for different organ systems. The determinants over a year in moist soil. These oocysts undergo sporula• of specific organ involvement are unclear. Parasitization tion over 2-3 days after excretion and become infective. is most common in the brain, heart, lungs, pericardium, This form can be ingested directly by humans (fecal-oral and lymphoid tissues. ISS Trophozoites and cysts coexist route) to initiate infection in the human (intermediate) during active infection, and tissue cysts persist after the host. Infected oocysts are killed by boiling or adequately clearance of an acute infection. cooking (over 65°C) meats or vegetables. The incidence and virulence of Toxoplasma infec• Proteolytic disruption of oocysts or of tissue cysts tions vary by region. In Europe, seroprevalence ap• occurs after ingestion. The released sporozoites are mo• proaches 75%, while estimates in the United States vary tile and penetrate nucleated cells throughout the body via from 5% to 40%. Clinically apparent infection occurs in direct invasion of local intestinal epithelial cells or to up to 30% of T. gondii-seropositive, HIV-infected indi• distant sites via the bloodstream and lymphatics. Sporo• viduals. While patients on maintenance therapy for tox• zoites mature into trophozoites within vacuoles of reti• oplasmosis do not develop Pneumocystis pneumonia, co• culoendothelial cells and of other tissues. 155 Trophozo• trimoxazole prophylaxis is incompletely protective ites are 4-8 J.Lm crescentic nucleated organisms that against activation of T. gondii. move by body flexion without a flagellum. These tro• T lymphocytes mediate much immunity to T. gon• phozoites multiply within a cell by internal division (en• dii, largely via the mechanism of macrophage activa• dodyogeny) until the cell ruptures, initiating a new cycle tion.IS9.160 Without specific activation, Toxoplasma of invasion. 155 In the face of an immune response and for blocks the fusion and acidification of phagolysomes. unclear reasons, infectious spread may be interrupted by Agents that interfere with either T-cell or monocyte func• the development of tissue cysts. These cysts are large (up tion (steroids, HIV, antithymocyte globulin, lymphoma) to 200 J.Lm) and contain thousands of slowly dividing, predispose to toxoplasmosis.IS9.161-174 Stimulation of relatively inactive trophozoites (sometimes called "bra• monocytes (IFN, interleukin-2, CSFs) by cytokines may dyzoites"). These cysts act as a reservoir of infection enhance killing of T. gondii.IS9.173 In the non-AIDS pa• throughout the life of the host. Rupture of cysts due to tient, the majority of cases of toxoplasmosis occur in pa• ingestion of undercooked meats or due to immunosup• tients with hematopoietic malignancy (lymphoma, leu• pression of the host initiates another cycle of infection. kemia) under chemotherapy (especially regimens including Tissue cysts can be disrupted by freezing and thawing or corticosteroids) and in organ transplantation recipients, by cooking. Bradyzoites are killed by heat and by normal notably of heart and bone marrow. 167.168.175-179 The pre• gastric secretions. dilection for CNS involvement suggests that immune clearance of T. gondii is less effective in the CNS. The 3.1.2. Epidemiology roles of antibody and complement in the killing clear• ance of T. gondii remain uncertain, although the combi• The infected cat produces millions of oocysts each nation can kill extracellular trophozoites. The develop• day for a period of up to 3 weeks. The organism has been ment of T- and B-cell immunity to T. gondii coincides found in most animal species that consume either plants with the clearance of extraneural organisms, the regres• or meat. Up to 25% of lamb and pork have been shown sion of tissue invasion, and the development of tissue to contain tissue cysts. Uncommonly, Toxoplasma has cysts. been isolated from beef, goat's milk, and eggs, as well as from vegetables consumed by seropositive vegetarians. Toxoplasma gondii is found worldwide. Seropositivity 3.2. The Patient increases with age. IS3 Infectious oocysts may be carried Toxoplasmosis occurs with four distinct clinical by coprophagous organisms including cockroaches, presentations: (1) congenital, (2) acquired in immu• flies, worms, and snails. Significant infection has oc• nocompetent individuals, (3) disseminated in immu• curred in laboratory workers who have become inocu• nocompromised individuals, and (4) as reactivation of lated with organisms. Toxoplasma has prolonged surviv• latent infection within the eye (ocular toxoplasmosis). al in refrigerated blood samples and may be transmitted by transfusion of either whole blood or white blood cells. 156 Transmission of toxoplasmosis has occurred in 3.2.1. Congenital Toxoplasmosis the setting of organ transplantation into a seronegative recipient as well as by reactivation of latent disease by Congenital infections result from acute infections immune suppression. 157 There are multiple subpopula- during pregnancy. They are usually asymptomatic infec- PNEUMOCYSTIS CARINJI AND PARASITIC INFECTIONS 299 tions occurring in immunocompetent individuals. How• 3.2.3. Ocular Toxoplasmosis ever, infected women who become immunocompro• mised may reactivate infection and transmit the organism Toxoplasma gondii is a common cause of cho• to the fetus. Women who are infected and seroconvert rioretinitis throughout the world, usually as a result of prior to conception have a low risk of transmission to the reactivation of latent congenital infection. 16<}.17o,ls6 This fetus. The incidence of fetal infection resulting in abor• form of infection occurs in immunologically normal tion (stillbirth) or in significant congenital disease rises young adults, affecting the retina and underlying choroid during the course of pregnancy: from 25% in the first and presenting clinically as unilateral or bilateral cho• trimester to two thirds of third-trimester fetuses. While rioretinitis. Congenital ocular toxoplasmosis may cause the incidence of infection is quite high, the majority of developmental abnormalities of the optic neuraxis, in• infants infected during the latter trimesters do not show cluding such common manifestations as strabismus, cat• signs of infection, and treatment of the mother with spe• aracts, nystagmus, or optic neuritis. The characteristic cific antibiotics significantly reduces the incidence of lesion on funduscopic exam is a cluster of areas of focal congenital infection (by over 50%). necrotizing retinitis, giving a white-to-yellow raised cot• The primary manifestations of congenital disease ton patch with blurred margins. Healing lesions are ini• are of CNS disease, particularly chorioretinitis or hydro• tially pale and gradually take on black pigment. Occa• cephalus. Sequelae of infection may not be immediately sionally, associated acute panuveitis, papillitis, or optic evident at birth. Children may have blindness, psycho• nerve atrophy may occur. Recurrent disease is common motor or mental retardation, jaundice, thrombocytope• (up to 30% after specific chemotherapy), often in areas nia, anemia, encephalitis, microcephaly, hypothermia, of scars from previous infection. Ocular toxoplasmosis or pneumonitis. Most of these congenital malformations usually occurs in the absence of systemic symptoms. are not specific to T gondii, but are related to inflamma• Bilateral infection is characteristic of congenital disease, tion and scarring in the sites of greatest infection. Mild while acute disease is usually unilateral. Distinctive disease is seen restricted to hepatosplenomegaly or characteristics of ocular toxoplasmosis include the clari• lymphadenopathy. These individuals may ultimately de• ty of vitreous and aqueous humors, the presence of bilat• velop CNS disease. It is currently thought that most chil• eral macular involvement, and the appearance of a nor• dren infected in utero will develop some disease related mal retinal exam in the presence of focal areas of retinal to congenital toxoplasmosis. degeneration.

3.2.2. Acquired Toxoplasmosis in 3.2.4. Toxoplasmosis in Immunocompromised Immunocompetent Individuals Hosts

Over 80% of individuals with Toxoplasma infection The true incidence of toxoplasmosis in immu• will be asymptomatic. Alternatively, toxoplasma will nocompromised hosts is unclear. Toxoplasmosis of the present with nontender lymphadenopathy affecting cervi• immunocompromised individual is usually due to the cal lymph nodes or systemic lymph glands. ISO-IS4 In this reactivation of latent infection in the absence of a limit• setting, toxoplasmosis may be confused with a "flu-like" ing immune response. Acute infection in this population syndrome or infectious mononucleosis. Atypical features generally results from organ transplantation or the direct such as those seen in lymphoma may include fever, hep• infusion of contaminated blood or blood prod• atosplenomegaly, atypical lymphocytosis, sweats, mus• uctS. I71 ,17S,I77,187-192 The occurrence of toxoplasmosis cle aches, sore throat, and maculopapular rashes. The in a seronegative individual in the absence of organ or lymph nodes may be tender, but rarely become fluctuant blood transfusion is uncommon. Blood products from without superinfection. Rarely, chorioretinitis may occur patients with chronic myelogenous leukemia (CML) tend in acute infection. While the clinical course is relatively to maintain high levels of parasitemia despite high anti• benign, symptoms may persist for up to a year. Fluctuat• body titers. Because of the survival of organisms in ing adenopathy and persistence of lymphadenopathy is stored citrated blood for up to 2 months at 4°C, patients occasionally seen. More severe disease involving the with CML should not be used for blood or organ dona• heart, lungs, and CNS is rarely observed. ISS Because of tion. The serologic status of organ donors should be the broad differential diagnosis of lymphadenopathy syn• assessed prior to transplantation. dromes, the diagnosis of toxoplasmosis is dependent on Because of the large number of protean manifesta• serologic testing or the identification of organisms. Oc• tions of toxoplasmosis, this infection must be considered casionally, lymphadenopathy is not significant in the set• in the differential diagnosis of many systemic illnesses in ting of multisystem involvement including hepatitis, the immunocompromised host. The non-AIDS immu• myositis, or fever of unknown etiology. nosuppressed patient is more likely to have some of the 300 CHAPTER 10 systemic manifestations of toxoplasmosis than are seen In the AIDS population, lymphadenopathy is com• in the immunocompetent host. A "mono"-like prodrome monly due to HIV; lymph node biopsies generally aie with fever and lymphadenopathy may precede other not diagnostic. The occurrence of disseminated Tox• manifestations. In this setting, disseminated infection oplasma infection is usually correlated with low circulat• will involve the brain, liver, bone marrow, heart, omen• ing CD4+ lymphocyte levels «50). Toxoplasma en• tum, spleen, and other organs. Multiple brain lesions are cephalitis is a common presentation for patients with common. The presentation of toxoplasmosis in the im• AIDS. Between 5% and 50% of seropositive HIV• munodeficient host is often that of encephalitis, with infected individuals may develop CNS toxoplasmosis, diffuse CNS impairment or multiple focal neurologic based on autopsy studies. AIDS patients from endemic deficits. 186 Some 10% (United States) to 25% (Europe) areas due to consumption of undercooked pork or lamb of acutely infected immunocompromised individuals or contaminated vegetables are at particular risk. In pa• will have a neurologic presentation (see below). Pulmo• tients from such areas (e.g., Haiti, much of Africa), T. nary infection may also be significant. 193.194 The clinical gondii infection is a commonly diagnosed opportunistic onset of pneumonia is associated with fever, dyspnea, infection in individuals with AIDS. Signs of meningitis cough, and occasionally hemoptysis. Chest X rays reveal are uncommon, while seizures, confusion, depression, a diffuse bilateral pulmonary infiltrate with atypical fea• visual changes, and hydrocephalus are more common. tures. In this setting, it should be possible to isolate The CNS lesions of toxoplasmosis must be dis• organisms from lung washings.195 In the organ trans• tinguished from other infections or tumor (Fig. plant recipient, a similar pattern emerges, with the ex• 8).175.197-205 The infection can be either focal abscesses ception that the disease may be due to dissemination or diffuse meningoencephalitis, based on the distribution from the transplanted organ. 157.168 Recipients who de• of the preexisting latent lesions. Acute, primary tox• velop infections are generally seronegative. This form of oplasmosis has also been reported. The presentation can infection is seen most often in cardiac transplantation, be as mild as slightly altered mental status, minor neuro• given the predilection of the organism for the myocar• logic signs, or fever with headache. Seizures and gross dium. Identification of organisms, including tissue cysts, motor deficits may occur in up to 10% of individuals. in a seronegative individual should raise the specter of The progression of Toxoplasma-induced mental status acute disseminated disease. changes is subacute when compared to that due to HIV In AIDS patients, as in most immunocompromised alone. HIV leukoencephalopathy or progressive multifo• individuals, toxoplasmosis is usually disseminated at the cal leukoencephalopathy (PML) forms part of the "AIDS time of presentation. 196.197 dementia complex," which can also present with focal or

FIGURE 8. Hematoxylin-eosin stain of a brain biopsy specimen from the edge of a large anterior brain abscess from a patient with AIDS. A tissue cyst contains multiple intracystic bodies or bradyzoites consistent with a diagnosis of toxoplasmosis. PNEUMOCYSTIS CARlNlI AND PARASITIC INFECTIONS 301 global CNS deterioration and may coexist with acute infections of the brain. Some of our patients have pre• sented with multiple organisms in a single small brain abscess, including T gondii with anaerobic bacteria, As• pergillus species, and mycobacteria, including tuber• culosis and M. avium complex. Because serologic test• ing in immunodeficient patients often is not helpful in establishing a diagnosis of toxoplasmosis, biopsies of infected areas may be required to confirm a diagnosis.

3.3. Diagnosis

3.3.1. Laboratory Evaluation for Toxoplasma gondii

The diagnosis of infection due to Toxoplasma is difficult, most notably in the immunocompromised indi• vidual, in whom early diagnosis is most important and serologic tests are least helpful. 206 Demonstration of the tissue cyst form of the organism or of a positive serum IgG level suggests the possibility of infection due to T gondii, but does not prove toxoplasmosis. Tissue cysts persist in the brain, lung, liver, lymph node, heart, and spleen for years after acute infection. The presence of trophozoites in lymph node, blood, brain, cerebrospinal fluid (CSF), or other tissues during acute infection, or the FIGURE 9. CT scan from the patient in Fig. 8 reveals multiple and demonstration of an acute (IgM) immune response to the bilateral contrast-enhancing brain abscesses surrounded by edema. This presentation is seen in T gondii infection more often than the large organism, is needed for confirmation. solitary lesions often associated with CNS lymphoma. Brain disease features prominently in the presenta• tion of immunocompromised patients with toxoplasmo• sis (Figs. 8 and 9).202 Decisions about the management lomyelitis, or mass effect due to brain abscess, the pa• of suspected toxoplasmosis involving the brain are com• tient may present with pneumonitis, myocarditis, or plicated by the risk of performing definitive diagnostic signs of hepatitis. Toxoplasma gondii trophozoites are procedures, including lesion aspirates or open brain occasionally found in lung lavage or lung biopsy sample biopsies, and the potential for toxicity of antibiotics (no• from patients with pneumonitis. tably pyrimethamine or sulfa), which approaches 50% with the antibiotics commonly used in AIDS patients. 3.3.2. Radiology The lumbar puncture is nondiagnostic in most cases. The CSF will have slightly elevated protein levels and few Radiologic evaluation will generally begin with a white blood cells. These patients will have a normal to head CT scan and chest radiograph. The chest radio• slightly decreased glucose concentration in the CSF; .hy• graph is nonspecific, the picture being that of prominent poglycorrachia is usually associated with the rupture of hilar lymphadenopathy with diffuse interstitial infiltrates. organisms directly into the CSF. Elevations in antibodies Like other atypical pneumonias, atypical patterns includ• to T gondii in the CSF are highly suggestive of acute ing nodules and assymmetric patches are common. Cavi• infection. tation or pleural effusions are uncommon. Chest radio• Empiric therapeutic trials are frequently the best graphs do not tend to improve over a 14-day course of approach in stable patients. In the presence of rapidly therapy unless corticosteroid therapy is employed. progressive brain lesions, clinical deterioration, lesions In AIDS patients, the presence of multiple and bi• unresponsive to empiric therapy, or serologic testing not lateral intraparenchymal lesions that are contrast• consistent with the clinical picture, a brain biopsy may enhancing on CT scans is often considered diagnostic allow the definitive separation of toxoplasmosis from of CNS toxoplasmosis (Fig. 9).207.208 CT studies of other processes. Biopsy of brain lesions has the added AIDS patients with solitary CNS lesions show that about advantage of identifying other potentially treatable pro• half will be due to T gondii, with the balance being cesses. In addition to meningoencephalitis, encepha- lymphoma, progressive multi focal leukoencephalopathy 302 CHAPTER 10

(PML), and, less commonly, other infectious or malig• ted tissues may be improved by immunostaining ampli• nant processes. 20S Non-AIDS patients will also have fication using peroxidase~antiperoxidase, fluorescent multiple CNS lesions, but the differential diagnosis must antibody, or ELlS As using unfixed tissues. All have be broadened and invasive diagnosis considered earlier proven useful clinically. in the course. Up to 20% of patients will have single In the normal individual, the histopathologic lesions without contrast enhancement. Occasionally, up• changes seen in the lymph nodes are often diagnos• take of contrast dye may be delayed. Repeat scans after tiC. 18 I.183,211 Epithelioid histiocytes appear in clusters, the administration of increased doses of contrast dye may monocytes infiltrate the sinuses, and reactive hyperplasia demonstrate lesions not previously observed on routine is observed. Organisms and giant cells are rarely seen. In scanning. CT scans without contrast are usually nega• the eye, retinitis with necrosis, vascular proliferation, tive. The majority of lesions are nodular or ring• and granulomata are seen. Myositis may be seen in any enhancing and have a predilection for the basal ganglia muscle, but is most prominent in the heart. Diffuse and the gray~white junction. Most lesions, especially patches of mononuclear infiltration may occur in the those of the posterior fossa, are better seen on MRI scan, presence or absence of organisms. Diffuse meningoen• which may reveal multiple, bilateral, small lesions not cephalitis will produce multiple areas of necrosis, partic• seen by CT. Often seen are large focal abscesses that ularly of the gray matter and microglial nodules. Organ• cannot be distinguished from necrotic tumor or abscesses isms are found within blood vessel walls, surrounding due to other pathogens. Serologic testing, when positive, areas of necrosis, and in normal tissues. Periventricular is most useful in this latter group. Radiologic evidence of lesions are more often seen in infants, accounting for a encephalitis is seen less frequently. high incidence of hydrocephalus. In the immunocom• promised host, many small areas of coagulation ne• 3.3.3. Histopathology and Culture crosis may be seen; large abscesses occur in some pa• tients. The identification of T. gondii in clinical specimens In contrast to the lesions produced in other organs, is difficult. In general, organisms are not found in body T. gondii usually evokes diffuse disease in the lungs. fluids; they may be found in cytology specimens from This result may reflect the role played by the lungs as a lung washings or CSF or as "contaminants" of viral tis• filter for circulating organisms and the extensive resident sue cultures.209.210 Impression smears of the tissues can phagocyte population. 193, 194 The pneumonitis is pre• be stained with Giemsa stain to demonstrate both the cyst dominantly interstitial and characterized by an infiltrate and trophozoite forms. Tissue cyst walls are stained by of macrophages, lymphocytes, plasma cells, and, occa• PAS stain (see Fig. 8). Trophozoites are stained with sionally, polymorphonuclear leukocytes. The local in• either Wright or Giemsa stains and by fluorescent or flammatory response is usually mild. Areas of bronchop• peroxidase-tagged antibody to T. gondii on histologic neumonia, endarteritis, and necrosis may develop. sections. The presence of multiple tissue-cyst forms in Discrete areas of interstitial infiltration may progress to areas of acute tissue inflammation in the absence of other areas of consolidation with necrosis or infarction. Prolif• pathogens may be used as presumptive evidence for the erating stages of T. gondii are seen inside alveolar mac• presence of acute infection. Tissues or fluids inoculated rophages and in the alveolar space. With active myocar• into mice have also been used for detection of T. gondii ditis, organisms can also be found in the endocardium. infection. This method is not practical for routine clinical Death may result from hepatic necrosis, cardiomyopa• diagnosis. Further, mice generally do not die from hu• thy, or secondary pUlmonary edema. As in the brain, man Toxoplasma infection; serologic testing and pathol• toxoplasmosis may occur in the setting of other oppor• ogy are generally necessary to confirm the diagnosis of tunistic infections including P. carinii pneumonia, bacte• toxoplasmosis using this system. Tissue culture methods rial pneumonia, or fungal abscess. have been improved with the identification of plaques in cell culture monoloayers and are more generally avail• 3.3.4. Immunologic Diagnosis able. Growth of T. gondii from blood in tissue culture can be considered evidence of disseminated infection. Skin testing for delayed hypersensitivity is not use• Isolation of viable organisms from tissue does not assist ful in establishing the diagnosis of acute toxoplasmosis. in determining the acuteness of infection. Toxoplasma Positive skin tests may not develop for months after gondii organisms are uncommonly found in lymph nodes acute infection and may never develop in immu• outside acute infection, but may be found in other tissues nocompromised patients, including those with AIDS. for months after therapy. The identification of organisms Skin testing may provide an alternative to serologic test• in fetal tissue or from the placenta is diagnostic of con• ing for popUlation screening. Similarly, lymphocyte genital infection. The detection of Toxoplasma in infec- transformation using patients' cells stimulated with Tox- PNEUMOCYSTIS CARlNll AND PARASITIC INFECTIONS 303

TABLE 7. Serologic Assays for Toxoplasma gondii Infectiona

Titer

Test Acute Chronic Comments

Sabin-Feldman dye test (IgG) 2: I: 1000 1:4-1:2000 Remains elevated; onset 1-2 weeks Indirect ftourescent antibody 2: 1: 1000 1:4-1 :2000 Remains elevated; onset 2-3 weeks; some false- (IFA)-lgGh positives" IFA-IgMh 2: 1:64 0-1:20 Negative in months; first positive acutely (1 week) Direct agglutination test (lgG) 2: 1:1000 to 2: 1:20 2: I :64,000 Remains elevated; BMEc to block IgM agglutination Indirect hemagglutination 2: 1:1000 I: 16-1:256 Remains elevated; delayed onset (!HA) (IgG) Complement fixation (lgG) 2: 1:32 0-\:8 Remains elevated; onset 2-3 weeks ELiSAh-double sandwich• 2:1:256 (or 2:1.7 units) 0-\:256 (1.7-3.0) Remains elevated; early onset; sensitive IgM Immunosorbent (lgM) (latex Positive Positive Simple, sensitive (vs. IFA); fewer false-positives bead) aA 2-tube or four-fold risc in titer to "acute" level is diagnostic for any test. Positive/diagnostic values for the various tests will vary among clinical laboratories, and some patients will fall outside these ranges. These represent adult values. l>May give a false-positive value in the presence of rheumatoid. antinuclear, or other autoantibodies; a single high titer is diagnostic of acute infection. cBME, f\-mercaptoethanol.

oplasma antigens is also an indicator of previous expo• pared with serum may be used to indicate the presence of sure to T. gondii. Inversion of the T-Iymphocyte help• primary infection of the CNS.186,215,216 er/suppressor ratio (an excess of suppressor T cells) is Specific diagnostic tests merit comment. Positive occasionally observed in the presence of acute tox• values must be established for each laboratory. The stan• oplasmosis. Such an inversion also occurs in the pres• dard serologic assay is the Sabin-Feldman dye test, ence of viral infection, including HIV and CMV, and in a which can be standardized to reference sera available variety of other conditions. The demonstration of circu• from the World Health Organization.214.217 Like most of lating antigen from T. gondii in sera is not routinely the tests that measure primarily IgG antibodies, positive available, but may be helpful in establishing the acute• tests do not occur until after 2 weeks of infection, with ness of exposure. 212 ,213 peak titers occurring at times up to 2 months. While titers decline over 1-2 years, low titers persist for life. 3.3.4a. Antibody Detection Tests. In the im• As with all serologic tests, the titer of antibody does not munologically intact individual, serologic testing is diag• correlate with the severity of illness, but may provide nostic for T. gondii infection (Table 7).184.214 The immu• information about the ability of the host to respond to nocompromised host will often fail to generate a specific new antigenic challenge. Because immunity to tox• antibody response to acute infection, or this response oplasmosis is largely T-cell-mediated, the presence or will be much delayed. In the patient receiving immu• absence of antibody will not determine the ability of the nosuppressive therapy, false-positive serologic tests may host to respond to acute infection. The IgM titer corre• occur in the setting of organ transplantation into se• lates most closely with acute infection; a number of tests ropositive organ recipients. These include both IgM and have been developed for this purpose. 218 .219 The direct IgG antibodies. The absence of diagnostic serology may agglutination test using either fixed whole trophozoites increase the need for a tissue diagnosis in the immu• or antigen-coated latex particles, the IgM immu• nocompromised host. In the immunodeficient individual, nofluorescent antibody test, and the conventional IgM the presence of a positive test is still of clinical impor• ELISA all give false-positive results in the case of high tance. Because much of acute toxoplasmosis occurs in endogenous levels of nonspecific IgM, rheumatoid fac• seropositive individuals, the value of serologic diagnosis tor, and antinuclear antibodies. 220-223 The double• in the absence of an elevation of the serum IgM titer is sandwich IgM ELISA and IgM immunosorbent assay questionable. However, conversion from seronegative to using solid phase do not suffer from such false-positive seropositive or the presence of a fourfold rise in titer can results and have much greater sensitivity than the altema• be taken as indicative of acute toxoplasmosis for most of tives.218.222-224 In the immunocompetent individual, the tests currently available. The currently available tests acute infection should be accompanied by seroconver• are summarized in Table 7. The presence of a differential sion from negative to positive or by the demonstration of concentration of specific antibodies in CSF when com- a fourfold (2-tube) rise from a low chronic titer to a high 304 CHAPTER 10 acute titer in sera drawn at least 3 weeks apart and run 3.4. Therapy of Toxoplasma gondii Infection simultaneously. If initial sera are drawn too late in the course of infection, such diagnostic increases may be Initial therapy for T. gondii infection should include missed. a reduction in the immunosuppressive therapy, when possible. Cellular immunity is needed to eradicate intra• 3.3.4b. Diagnosis in the Immunodeficient Pa• cellular organisms. Extracellular organisms are killed by tient. In the immunodeficient host, rapid progression of antibody in conjunction with complement, while cyst disease or atypical presentations may necessitate tissue forms are largely resistant to antibiotic therapy. Empiric diagnosis. 225 Many patients will fail to demonstrate a therapy should be initiated in patients with significant rise in IgM serum titer. In AIDS patients, there may be clinical disease who are at risk for disseminated tox• some advantage to the solid-phase IgM immunosorbent oplasmosis. Such conditions include CNS, pericardial, assay that is available commercially. The failure of se• pulmonary, hepatic, splenic, or blood-borne disease in rologic testing points out the importance of obtaining patients with AIDS, high-dose corticosteroid or cyclo• baseline titers of Toxoplasma antibodies in AIDS or or• sporine therapy, bone marrow transplantation recipients, gan transplant patients. Demonstration of relatively en• or acute hematopoietic malignancy. 206,209,225-229 hanced antibody production in the CSF has been associ• Antibiotic therapy is outlined in Table 8. A syner• ated with Toxoplasma encephalitis. Local antibody gistic combination of antibiotics including pyrimeth• production should be associated with a specific antibody amine and sulfonamide or cIindamycin is favored for level (as a fraction of total local IgG) greater than that Toxoplasma infection in all patients. Recent data in fraction of specific antibody present in serum (as a frac• AIDS patients suggest that oral clindamycin (600 mg PO tion of total serum IgG). A similar concept has been q6hl may be as effective as high-dose intravenous drug applied to the diagnosis of ocular toxoplasmosis, in (i.e., 1200 mg IV q6h).227-231 The most common sul• which serum titers are typically low. In some hosts, nota• fonamide used is sulfadiazine, but it is interchangeable bly in newborns and in recent organ transplant (espe• with trisulfapyrimidine for this purpose. 228 Other sul• cially cardiac) recipients, elevated titers of anti-Tox• fonamides are not equally effective. oplasma antibody may be normal. IgG antibody titers in Non-AIDS immunodeficient patients do better in newborns may reflect maternal antibody titers. In con• general than AIDS patients suffering from disseminated genital infection, the child may not produce specific anti• toxoplasmosis. The main limitation of therapy in AIDS bodies before 2-9 months of age. Serial tests may be is drug toxicity, which occurs in at least half of individu• helpful in this situation. Cardiac and heart-lung trans• als. Discontinuation of therapy is generally associated plant recipients may demonstrate significant titers even with a relapse of brain disease. Our own experience has without acute infection. Elevated CSF IgM levels should supported lifelong therapy in AIDS patients. Relapse has always be taken as indication of possible brain involve• been observed during prophylactic therapy with py• ment. rimethamine, trimethoprim-sulfamethoxazole, and spi-

TABLE 8. Antibiotic Therapy for Toxoplasma gondii Infections"

Drug b Dose Duration Comments

Pyrimethamine 100 mg PO X 2 Load Bone marrow suppression: May give folinic acid 5 mg and Then: 25-50 mg PO gd or god 3-6 weeks PO/1M god except in leukemia Sulfonamide Sulfadiazine 4 g PO Then: I-\.5 g PO gid 3-6 weeks Decrease dose for neutropenia; sulfa allergy common or or Trisulfapyrimidine 75-100 mg/kg/day Spiramycin I g PO tid or gid 3-6 weeks In pregnancy or sulfa allergy with pyrimethamine; CNS data or limited Clindamycin 600-1200 mg IV q6h 3-6 weeks Slower resolution than with sulfa; C. difficile colitis ur 600 mg PO q6h uActiVl: infection: Twice-weekly blood counts arc necessary to detect bune marrow suppression due to therapy. Lifelong proph).rJaxis after therapy for acute infection is recommended in AIDS patients. See Section 3.7 for preferred therapies. !>Investigational: trimctrcxate. BW566c80 (atavaquone), macrolides, IFN-"y. PNEUMOCYSTIS CAR/Nil AND PARASITIC INFECTIONS 305 ramycin. 206.23 1.232 Higher-dose pyrimethamine (50-75 diseases. Given the long serum half-life of py• mg/day) has been used in some AIDS and transplant rimethamine, a regimen of 3 days a week is generally patients for therapy and prophylaxis to increase serum adequate for the prevention of disease. Alternatively, levels of antibiotic. In general, folinic acid supplementa• Fansidar can be given at a dose of 1 or 2 tablets per week tion is needed. Newer therapies that have promise and in many patients. The incidence of toxoplasmosis is re• are under study include atovaquone, trimetrexate, and duced in AIDS patients receiving cotrimoxazole pro• the new macrolides roxithromycin, azithromycin, and phylaxis. Breakthrough infection has occurred during clarithromycin in combination with sulfonamide or py• therapy with this antibiotic combination. rimethamine.233.234 These latter agents have the advan• tage of excellent tissue penetration in excess of serum Illustrative Case 2 levels. Atovaquone may also have some activity against tissue cysts. In AIDS patients with toxoplasmosis, some A 37-year-old man was brought to the Massachusetts General early relapses have been seen with the macrolide regi• Hospital Emergency Ward because of progressive inability to care for mens. 232 In combination with pyrimethamine, skin rash himself. The patient was a homosexual whose single sexual partner had (38%), OJ (38%), liver function test (77%), or hema• died of AIDS 15 months previously. At that time, the patient was serum HIV-negative by ELISA. By history, the patient had been well until 3 tologic (54%) toxicities are seen. Success is directly pro• months prior to admission, holding full-time employment as a portional to the penetration of the agent into the eNS and computer programmer. He had complained of some decreased "ability the patient's ability to tolerate drug side effects. Bone to concentrate" and of mild fatigue. These symptoms were attributed marrow suppression and skin rashes are common. In the by the patient to depression following the anniversary of his partner's setting of other immunosuppressive therapies or antiviral death. Two weeks before presentation, he had seen his personal physi• cian for a general examination. This physician had detected mild dif• therapies, some patients will tolerate slightly reduced fuse and nontender lymphadenopathy and noted that the patient seemed sulfonamide doses or use of another sulfonamide prepa• "tired" but otherwise normal. A serum HIV screening test had been ration in therapy or prophylaxis, rather than its being positive by ELISA and confirmed by "Western blot"; the patient had necessary to discontinue an agent that is causing minor not yet been notified. A serologic test for toxoplasmosis revealed a side effects. While the use of corticosteroids may reduce positive IgG titer (I: 1024) and a negative IgM titer. On the day of admission, the patient had not appeared at work and had been found mass effect and brain edema in the acute phase, it is not comfortable but somewhat confused at home. He had no pets and no clear that there is a role for these agents in the long-term other known infectious exposures. management of toxoplasmosis. 170 Immune modulators, On examination, the patient was thin, but in no acute distress. He including IFN-"{, may be useful as adjuncts to antibiotics complained of a mild headache, but denied fevers, photophobia, or in clearing intracellular organisms. meningismus. On neurologic examination, the patient's short-term memory was impaired, and he forgot the ends of some sentences. His Therapy should be adjusted to the underlying im• speech was fluent. He was not able to recognize some objects or written mune disorder. 225 For most immunodeficient patients, words. His general examination revealed mild lymphadenopathy and a pyrimethamine is given for up to 6 weeks at 25 or 50 palpable spleen tip, but was otherwise unremarkable. Laboratory eval• mg/ day. In AIDS patients, 50-100 mg/ day is preferred. uation revealed a total white blood cell count of 2300 with a normal In most patients, this drug will induce bone marrow sup• differential and 137 CD4+ lymphocytes. His hematology, chemistries, and chest radiograph were otherwise within normal limits. A head CT pression, which may be relieved by calcium leucovorin. scan was performed that demonstrated multiple (at least three), bilat• Some patients will experience an altered taste sensation, eral, contrast-enhancing, ring-shaped lesions with surrounding edema headaches, or GI upset while taking pyrimethamine. The (Fig. 9). A lymph node biopsy revealed only reactive hyperplasia. sulfa drugs are given at a daily dose of up to 8 g after a On the basis of the presumed diagnosis of toxoplasmosis, the loading dose of 4 g. The patient must be well hydrated to patient was treated empirically with pyrimethamine and sulfadiazine and switched to clindamycin and pyrimethamine when a drug rash prevent crystalluria. Alternative therapies are less toxic developed on day 5 of therapy. Because of progressive neurologic and less active. 235 AIDS patients and some organ trans• deterioration in the absence of improvement by CT scan, a stereotactic plant recipients may require prolonged prophylactic ther• brain biopsy of one of the brain lesions was performed. Toxoplasma apy.206 Most of the AIDS patients at risk for relapse of gondii was demonstrated (Fig. 8). On antibiotics, the patient improved toxoplasmosis are also at risk for other infections, in• only slightly over 6 weeks of therapy. A repeat CT scan revealed some improvement in some of the lesions, but a large frontal lesion remained cluding P. carinii pneumonia. Seronegative recipients of unchanged. Biopsy of the anterior lesion revealed B-cell lymphoma. heart transplants from seropositive donors should receive This tumor progressed rapidly despite therapy. The patient died 3 6-8 weeks of pyrimethamine (50 mg/day) with sul• months later. fadiazine (2-4 g/ day) or clindamycin (1200-1800 Comment. The presentation of toxoplasmosis of the CNS can be mg/day).I78.236 Like Toxoplasma, Pncumocystis can be subtle. The HIV-positive patient is often well-appearing, without fever or headache. Up to 60% will have focal neurologic deficits, fever, prevented by the chronic use of a regimen containing altered mental status, or seizures. The geographic distribution of infec• sulfa drug. 228 The use of pyrimethamine (50 mg/day) tion varies with the incidence of T gondii infection in the general and sulfadiazine (2 g/day) successfully prevents both popUlation. While toxoplasmosis is an uncommon presenting mani- 306 CHAPTER 10

festation of AIDS in the United States (3-5%), up to a third of se• Immunocompromised individuals, including bone mar• ropositive AIDS patients will eventually develop disease without pro• row transplantation recipients, renal transplant recipients, phylaxis. The clinical presentation of toxoplasmosis in the AIDS pa• individuals with primary immunoglobulin deficiencies, as tient is often indistinguishable from "HIV-encephalitis," CNS lymphoma, or progressive multifocal leukoencephalopathy (PML). well as patients with AIDS are candidates for severe, and The CT scan is often used diagnostically for T gandii infection. generally unremitting, gastrointestinal and gallbladder in• The presence of multiple and bilateral contrast-enhancing (nodular or fection. 254-256 Despite its growing importance, the patho• ring) lesions by CT or MRI scan is highly correlated with toxoplas• genesis of cryptosporidiosis has not been clarified. 257 mosis. Howevcr. lymphoma can have the same appearance or. as in this case, can coexist with T Rondii infection. These tumors are often aggressive and poorly responsive to treatment. By MRI scan. PML 4.1. The Organism lesions usually cause multiple or diffuse subcortical changes of high intensity without gadolinium enhancement. A response to therapy for Many species of Cryptosporidium have been identi• CNS toxoplasmosis (encephalitis or brain abscess) is often seen clini• fied, based on the animal species in which they were cally within a week and radiographically in 2-3 weeks. Failure to identified. However, the ability to transmit these infec• improve on empiric therapy may necessitate further investigation. Toxoplasmosis is generally seen in AIDS patients with CD4 lym• tions between species, most notably between animals phocyte counts of less than 200/ml blood. The presentation can be and man, indicates that this zoonotic organism lacks host similar in non-AIDS immunocompromised patients, although fever and specificity.258 Two species appear to cause significant systemic signs are common. PML and lymphoma are also seen in organ disease in mammals: C. parvum and C. muris. C. par• transplantation recipients and following intensi ve chemotherapy for vum is somewhat smaller (2- to 3-f.Lm diameter oocysts) carcinoma. Infection occurs almost exclusively in (IgG)-seropositive individuals. An IgM response is often absent. Lifelong suppressive than C. muris (5 to 8-f.Lm oocysts). C. parvum is primari• therapy is needed in AIDS patients after the initial treatment. Break• ly responsible for the diarrheal disease of humans and of through infection has been seen in AIDS patients on prophylaxis for P. cattle, while C. muris infects primarily the stomach of carinii. nonhuman mammals. Some additional subspecies have been identified recently in stools of patients with AIDS. Additional antigenically distinct subspecies are begin• 4. Cryptosporidium Species ning to be identified in animals. The coccidia have generally similar life cycles. In• Cryptosporidium is a protozoan parasite that can fection is initiated by ingestion (fecal-oral route) or, cause severe and persistent diarrhea in patients with occasionally, by inhalation of oocysts. It is likely that the AIDS or neutropenic hosts and milder, generally self• oocyst can also initiate an autoinfectious cycle, Excysta• limited gastroenteritis in less severely immunodeficient tion releases four motile sporozoites that attach to and individuals and in the immunocompetent host. 6.237-244 penetrate the host epithelial cell where they mature into Despite the description of this organism in mice by trophozoites (Fig. 10), Asexual (schizogeny) division Tyzzer in 1907, the organism was not linked to signifi• produces up to eight merozoites that can either reinfect cant disease in animals until the 1950s. It is recognized host epithelial cells or initiate a sexual cycle (ga• as a major pathogen of turkeys, calves, and lambs. Se• metogeny), Sexual reproduction completes the cycle by vere cryptosporidial diarrhea was detected early in the producing mature oocysts, A fraction of the oocysts have AIDS, epidemic.7.245 In Africa and Haiti, AIDS• thin walls and rupture within the intestinal lumen to associated diarrhea presents as the constellation of find• reinitiate the cycle within the host. The majority are ings referred to as "slim disease": diarrhea, weight loss, excreted in feces, fatigue, fever, and, eventually, death.6.246-248 Up to Little is known about the pathogenesis of this infec• 40% of these patients' clinical manifestations may be due tion, Symptomatic disease is generally associated with to Cryptosporidium. 7,240.249 In the United States, car• infection of the proximal small bowel. The hepatobiliary riage of Cryptosporidium in AIDS patients is common tree may serve as a reservoir for reinfection in the immu• (up to 5%).238 Some 10-15% of patients with AIDS and nocompromised host. Carriage in the gall bladder has diarrhea will have cryptosporidiosis. 25o More recently, it been associated with failure to clear infections in both has been recognized as a common cause of enteritis AIDS patients and in children with hypogam• worldwide in immunocompetent hostS. 244 ,251-255 Cryp• maglobulinemia (Fig, 10). Shedding of cysts occurs in tosporidium has been detected in up to 5% of immu• individuals with and without immune compromise or nologically normal individuals experiencing gastroen• symptomatic diarrhea. teritis or chronic malabsorption. 244 In the individual with diarrhea containing Cryptosporidium, other organisms 4.2. Epidemiology are often detected, including amebae, CMV, Giardia lamblia, Isospora belli, and adenovirus. 250 Outbreaks of Improvements in the identification of Crypto• cryptosporidial infection have occurred in day care cen• .Iporidium have demonstrated the presence of organisms ters and subsequently in the families of affected children. in up to 32% of the population in some underdeveloped PNEUMOCYSTIS CAR/Nil AND PARASITIC INFECTIONS 307

FIGURE 10. Cryptosporidia from the gallbladderof a patient with AIDS. Electron micrograph. x7500.

nations and up to 20% of people in more developed The pathogenicity of zoonotic infections may be of lesser countries. The worldwide distribution of this disease is severity than those spread person-to-person. confirmed by the high incidence of this infection in pa• The susceptible patient includes the entire range of tients with AIDS: up to 20% will have identifiable organ• immune dysfunction, Significant cryptosporidial diar• isms and up to 5% will develop cryptosporidial enter• rhea has been seen in diabetics after gastrointestinal sur• itis. 2SO ,2S1 Cryptosporidia have also been detected in gery, in organ transplant recipients, in children with pri• symptomatic and asymptomatic patients with hema• mary immune deficiencies, in AIDS patients, and in tologic malignancies and other immune deficits,259,26o normal individuals. 239 ,256,264,265 Both humoral and cel• Cryptosporidium is probably a common cause of trav• lular immune mechanisms appear to be involved in, and elers' diarrhea. 261 Organisms are generally transmitted necessary for, protection against Cryptosporidium. 266 A by fecal-oral contamination, Waterborne transmission syndrome similar to cryptosporidiosis is seen in many has also been demonstrated, 262,263 Spread occurs be• patients with AIDS-associated enteropathy who have tween animals and between man and animals, Human• malabsorption and villous atrophy in the presence or to-human spread causes the epidemics seen occasionally absence of identifiable pathogens, 147,238,249 The signifi• in day-care centers and in families,2s3,264 Studies in im• cance of small numbers of organisms or of HIV itself in munocompetent patients demonstrated a range of 1,5- the pathogenesis of this syndrome remains unclear. 10% of diarrheal diseases is caused by cryptosporidi• osis.252 The Massachusetts General Hospital experience 4.3. Diagnosis has noted that about 3% of individuals with significant diarrheal illness will have Cryptosporidium identified in Cryptosporidium infection should be suspected in their stools in the absence of other known pathogens. any patient with profuse watery diarrhea, but primarily There is no gender preference, but about half are chil• in those in whom an underlying immunodeficiency has dren younger than 5 years of age, Clustering of cases been identified, It is probably worthwhile to exclude oth• appears to occur during later summer and the fall. Cryp• er possible etiologies of infection, More common infec• tosporidium oocysts have been found in rivers through• tions are those due to toxigenic E, coli, Salmonella, out the western United States and in sewage. It is likely Campylobacter, Shigella, and antibiotic-associated C. that the contamination is due in part to the relative resis• difficile. 6 ,237 Cholera and Yersinia may have a similar tance of this organism to traditional means of steriliza• presentation 267 Viral agents are more difficult to identi• tion of common source water supply, including chlo• fy, but it is likely that adenovirus, rotovirus, and Nor• rination, iodophors, hypochlorite, and formaldehyde. walk virus are more common pathogens. 268 Cyto• Animal-to-person spread is common in animal handlers, megalovirus is an important differential consideration in 308 CHAPTER 10 addition to, or as the primary agent, instead of Cryp• on Giemsa stain, using a light green counterstain. Im• tosporidium. 2IO Many parasites will cause diarrheal syn• provements in direct immunofluorescent antibody stain• dromes, including Giardia, amebae, Microsporidia, and ing may enhance detection. Antigen detection in serum Isospora. 269 ,270 is under development. Specimens should be handled Diagnosis may be made noninvasively by stool test• carefully due to the possibility of aerosolizing infectious ing. Because oocysts are similar in size to yeasts, identi• orgamsms. fication of Cryptosporidium requires special staining. Oocysts may be concentrated by the Sheather sugar cov• 4.4. The Patient erslip flotation method that allows quantitation and iden• tification of infectious organisms. This laborious method The patient presents with watery diarrhea, abdomi• has largely been replaced by modified acid-fast staining, nal pain, anorexia, nausea and vomiting, fever, and my• Kinyoun's carbol-fuchin negative staining, auramine algias. 275 Stool examination reveals watery stool without staining, and safranin staining. Also available are indi• blood or white cells, with intermittent shedding of large rect immunofluorescent staining with monoclonal anti• number of cryptosporidial oocysts. Severe diarrhea may bodies and experimental methods including direct immu• be associated with malabsorption, as measured by D-xy• nofluorescence and ELISA.271 Serological tests are lose of vitamin BI2 malabsorption, and steatorrhea. Mu• under development but have not been refined to allow the cosal thickening and small bowel dilatation may be noted diagnosis of acute infection. The immunocompromised in radiographic studies. Infection of the gallbladder is host with cryptosporidiosis will not develop a significant common. In the immunocompetent patient, the syn• serological response to the organism. It may be neces• drome should resolve in I to 3 weeks. Organisms may sary and worthwhile to proceed to small or large bowel continue to be shed after the resolution of symptoms. biopsy. Organisms and typical histopathology are better In the immunocompromised patient, recurrent dis• seen in the small bowel.27o.272 On biopsy, infection may ease may occur in the absence of therapy. Diarrhea may be patchy. Typically, there is a loss or blunting of the be significant enough to require hospitalization for dehy• villi; crypt abscesses develop in immunologically normal dration or wasting. The right upper quadrant localization hosts. There is an acute and chronic inflammatory re• of abdominal symptoms may suggest acute cholecystitis. sponse in the lamina propria. Standard hemotoxylin• The gallbladder may be dilated, with thickened walls and eosin stained specimens will reveal small organisms at dilated bile ducts. In the absence of cholangitis, the syn• the tips and between microvilli. Ultrastructural studies drome may be mimicked by a number of enteropathies in demonstrate the presence of an extracytoplasmic but AIDS patients, including that of primary HIV infec• intracellular parasitophorous vacuole in immuno• tion. 6. 7 .276 The severe diarrhea associated with cyto• compromised individuals. The range of histopathol• megalovirus infection in some patients with AIDS is oc• ogy is quite broad. Mild inflammation may progress to casionally bloody and may merit separate therapy. focal necrosis. Our experience suggests a synergistic in• jury between cytomegalovirus and Cryptosporidium. 4.5. Therapy of Cryptosporidium This affects colonic mucosa and also the esophagus, stomach, appendix, pancreatic and bile ducts, in the res• There is no useful therapy for cryptosporidiosis. piratory tract, and the gall bladder. A few AIDS patients Support with fluids and electrolytes and added nutrition have had cryptosporidial cholangitis in the setting of si• may be necessary. In immunosuppressed patients, the multaneous cytomegaloviral infection of the gall blad• disease will resolve if immunosuppressive regimens can der. When Cryptosporidium is detected in the lungs, it is be reduced or eliminated. Antimotility agents have not usually found in association with gastrointestinal cryp• been demonstrated to be effective. Preliminary encour• tosporidiosis. 273 ,274 In our experience, this has been seen aging results with the macrolide spiramycin (2-3 gm/ only in AIDS patients and probably reflects aspiration of day) have not been consistently reproducible. 277.278 Spi• organisms, rather than acute, primary pulmonary infec• ramycin does appear to have some efficacy in cryptospo• tion. 194 ridiosis in the non-AIDS immunocompromised indivi• As noted above, Cryptosporidium is detected by duals. The drug is poorly absorbed with food. Anecdotal either wet mount or fixed preparation of stool or other reports of adverse effects during therapy with high-dose excretions. The oocysts do not stain with iodine and are spiramycin (1.5 g every 8 hr IV) suggest that some pa• orange with Truant's auramine-rhodamine stains. Yeasts tients have had increased stool output and volume loss are brown with iodine and do not stain with Truant's. On with the development of fecal leukocytes, protein loss, fixed smear, oocysts stain red with dense internal gran• and progressive loss of mucosal folds in the presence of ules on Kinyoun stain, while yeasts stain green. The very few organisms. Occasionally, apotosis with loss of typical morphology of Cryptosporidium will also be seen columnar epithelium and vacuolization has been ob- PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 309 served. In AIDS patients treated with spiramycin, most sexual reproduction. Unsporulated oocysts are also continue to excrete organisms, but some have had remis• formed and are shed intermittently and mature outside sion of symptoms. Controlled studies of this agent do not the infected individual. Isospora is epidemic in tropical exist but are being conducted. Alpha-difluoromethyl• and subtropical areas, including parts of South America, ornithine (DFMO) also has demonstrated some palliative Africa, and Southeast Asia. Person-to-person spread effect on infection, but toxicities (largely bone marrow probably accounts for outbreaks seen in the institutional depression) have limited its use. Preliminary animal setting. Isospora has been demonstrated in 0.2-1 % of studies using hyperimmune sera against Cryptosporid• patients with AIDS in the United States, and in up to illm or bovine colostrum are encouraging, but efficacy in IS% in Haiti, but its true prevalence is not known. The humans has not yet been demonstrated.279.280 Bovine mechanism of acquisition of Isospora infection has not colostrum is inhibitory for cryptosporidial growth in vi• been clarified completely. It is likely that many carriers tro. A few patients have been treated with transfer fac• of the disease are asymptomatic. tor, diclazuril and leclazuril, but these agents have not proved useful in clinical trials. 5.2. The Patient Somatostatin has been useful in reducing the severi• ty of the secretory-type diarrhea in a few patients. 281 Isospora belli causes diarrhea in immunocompetent Octreotide is a somatostatin analogue (Sandoz Phar• patients, especially young children, and in AIDS patients maceuticals) that also has been useful in treating secre• and malnourished individuals. 24 1.285 The patient pre• tory diarrhea.282.283 In AIDS patients with refractory sents with watery, nonbloody diarrhea with nausea, ab• symptoms, stool frequency and volume often decrease dominal pain, and weight loss. Systematic signs (head• significantly during therapy with octreotide. Unfor• ache, malaise, myalgias, fever) are often present. tunately, patients with no identifiable organisms appear Prolonged infection may cause malabsorption. The in• to do better with this agent than do individuals with fection is self-limited in the normal host, clearing in 4-6 documented cryptosporidiosis. weeks. It is worth remembering that organisms shed by patients are infectious. Precautions are necessary to pre• vent spread from infected individuals within the hospital 5.3. Histopathology and Diagnosis setting. Diagnosis of isosporiasis is established by identi• fication of Isospora oocysts in fecal specimens in the 5. Isospora belli appropriate clinical setting. Organisms can be identified by the modified acid-fast stain, by sugar flotation, by Isospora belli is a coccidian protozoan that infects auramine-rhodamine stain, or by intestinal biopsy. His• the 01 tract of immunocompromised individuals. Like topathology of the biopsy specimen reveals mucosal at• Cryptosporidillm, Isospora was described in 1915, but is rophy, villous blunting, crypt hypertrophy, and inflam• mation of the lamina propria, primarily with eosinophils, still poorly understood. Isosporiasis is a common cause of diarrheal disease in tropical regions, but is found lymphocytes, and plasma cells. The organism is found in worldwide. 284 The common forms of disease are due to vacuoles within the cytoplasm of epithelial cells. Extra• I. belli and occasionally I. hominis. Both are normally of intestinal dissemination of the organism is rare. Multiple low pathogenicity. In industrialized regions, these organ• stool specimens may be necessary to demonstrate organ• isms because of small numbers of oocysts. Fecal leuko• isms can cause or contribute to disease in immu• cytes may be absent. Charcot-Leyden crystals are often nocompromised individuals. seen in stool samples. A duodenal aspirate may be useful in detecting organisms. Electron microscopy may be 5.1. The Organism: Life Cycle necessary to find organisms on colonic biopsy. There are and Epidemiology no useful serologic tests at present. A mild leukocytosis The organism completes its life cycle within the and eosinophilia may be seen in the peripheral blood human host, and both sexual and asexual cycles can con• smear. tinue indefinitely within the 01 tract. The infection is transmitted by an elliptical oocyst approximately 2S-30 5.4. Therapy f.Lm x 10-IS f.Lm in size. There are two internal sporo• cysts containing four sporozoites each. Ingestion of Isosporiasis responds to therapy with oral sporulated oocysts releases infectious sporozoites that trimethoprim-sulfamethoxazole (TMP-SMZ) at a dose invade the intestinal epithelium and undergo asexual and of 160 mg TMP component 4 times a day for 10 310 CHAPTER 10 days.285.286 In AIDS patients, prolonged additional ther• 6.1. The Organism apy with TMP-SMZ (twice a day for an additional 3 weeks) has been necessary for clearance of oocysts 287 Microsporidia have spores ranging in size from 1 to Prophylactic therapy with TMP-SMZ (once a day) or 20 f.Lm. 291 Spores infecting mammals are generally 1-2 pyrimethamine-sulfadoxine (Fansidar) has been useful f.Lm in diameter, requiring electron microscopy for iden• in preventing relapses. Other "successful" therapies may tification, using biopsy specimens or aspirates of affected be useful in part because of the treatment of other con• large or small bowel. These spores have thick walls, comitant infections. 286 Patients may continue to excrete allowing them to persist outside the host and also making organisms long after the successful completion of thera• them difficult to stain. They are generally gram-positive py. This observation probably supports the use of pro• and contain PAS-positive granules. Birefringent spores phylactic therapy in AIDS patients or other symptomatic will be found throughout the fibrous stroma, but will not immunocompromised hosts. stain on hemotoxylin-eosin stain. Organisms are found in the supranuclear cytoplasm of cells as binucleated spores containing a coiled polar tube. Small-bowel biop• sy reveals the greatest number of organisms. All the 6. Microsporidia developmental forms of the organism's life cycle occur within the epithelial cells of the small boweJ.292 Infec• The Microsporidia make up a phylum consisting of tion of the liver produces a granulomatous hepatitis. Or• approximately 80 genera and over 700 species of organ• ganisms can spread via blood, lymph, or infected macro• isms. These are obligate, intracellular, spore-forming, phages throughout the body. Significant accumulations protozoal parasites that were first identified in 1857 as have been found most often in brain or kidney. Brain causing disease in insects, fish, rodents, and some pri• infection results in focal seizure disorders, while kidney mates. These organisms were rarely implicated in clini• involvement may produce interstitial nephritis of some cal disease prior to the advent of AIDS. 288- 290 Case severity. In non-AIDS patients, a granulomatous vas• reports describe a series of children with seizure disor• culitis of cerebral vessels may produce a meningoen• ders and children and adults with corneal ulcerations, cephalitis. It appears that cell-mediated immunity is crit• keratitis, or iritis. Keratitis appears to be a rare mani• ical for protection against significant disease due to the festation of microsporidiosis of the immunocompetent Microsporidia. 288 host. Disseminated disease has been described in a young boy with thymic aplasia. Autopsy of this child 6.2. The Patient revealed disseminated Microsporidia involving the lungs, stomach, colon, kidneys, adrenal glands, heart, Like individuals with cryptosporidiosis and iso• liver, and other muscles. The organism was identified as sporiasis, patients with microsporidial infection present Nosema connori. Cases of microsporidiosis have been with chronic watery, nonbloody, nonmucoid diarrhea elicited by treatment with corticosteroids as well as in without fever. Patients have weight loss despite continu• other immunodeficient states. Corneal infections with ing to eat well. Intestinal mucosa are normal to mini• Microsporidia have been identified in both AIDS and mally inflamed endoscopically. Enterocyte degeneration non-AIDS immunocompromised patients. Microsporid• accompanies partial villous atrophy and modest inflam• ial infection has been identified in patients with AIDS mation in the lamina propria. By contrast, patients with since the mid-1980s as a cause of chronic diarrhea with "AIDS-associated enteropathy" without identifiable in• weight loss. 267.289 In general, the cause of this form of fection are more likely to have malabsorption, including infection has beel1 identified as Encephalitozoon bie• lactase deficiency, with minimal changes in villous mor• neusi, for which man is the definitive host. Up to 30% of phology. The possible mechanisms of this syndrome in• AIDS patients with weight loss and chronic diarrhea cludes bacterial overgrowth secondary to local immune have been found to be infected with Microsporidia in deficiency. some series. Disseminated disease in AIDS patients has involved skeletal muscle, kidney, liver, eye, and intesti• 6.3. Diagnosis and Therapy nal wall as well as intestinal epithelial cells. In this popu• lation, other genera have also been identified. These in• Suspicion of the presence of Microsporidia may be clude Pleistophora (a pathogen of fish and insects), raised by the presence of organisms seen on Brown• Encephalitozoon species (found in many mammals), and Brenn-stained tissue sections (Fig. II). The organism is Enterocytozoon cuniculi. Further genera have been iden• occasionally seen on Giemsa-stained impression smears tified in small numbers of patients. and on thin sections stained with methylene blue-azure PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 311

FIGURE 11. Microsporidia within the jejunal epithe• lium of a patient with AIDS (<---) are gram-positive spores by Brown-Brenn stain. x 1750. Courtesy of Drs. R. Weber and R. T. Bryan, Parasitic Diseases Branch, Centers for Disease Control.

II with a basic fuschin or toluidine blue counterstain. dotal efficacy. Symptomatic therapy is similar to that for Species identification requires electron microscopy.291 cryptosporidiosis (see Section 4.5). The increasing fre• Unconcentrated stool specimens or duodenal aspirates quency of isolation of Microsporidia from AIDS patients can be screened after fixation in 3 volumes of 10% for• (0-30%) varies with the region from which the patients malin or on thin smears made with methanol fixation. are derived and with travel to tropical regions. It is likely Staining with a mixture including chromotrope 2R (Har• that improved diagnostic techniques will further increase leco, Inc.) has been used by some workers in place of recognition of this phylum in many immunocompro• Giemsa, toluidine blue 0, Gram's stains, stool concen• mised hosts. tration, or electron-microscopic examination. 293 Non• AIDS patients have a more severe inflammatory response and greater destructive ulceration of corneal tissues dur• 7. Strongyloides stercoralis ing microsporidial infection. The diagnosis of micro• sporidium infection can be made by electron microscopy Since the original association of Strongyloides ster• of corneal or conjunctival scrapings. A variety of se• coratis with "Cochin China diarrhea" in 1876, stron• rologic tests have been developed to detect antibodies gyloidiasis has been recognized as an important human binding to spores and extracts of organisms. These tests intestinal pathogen. This nematode currently infects al• are being refined for clinical use. most 100 million people worldwide. 294 ,295 This parasitic There is no known therapy for microsporidiosis. helminth can complete its entire life cycle within the Albendazole (400 mg PO bid for 4-6 weeks) has anec- human host, allowing for persistent and occasionally 312 CHAPTER 10 lifelong infection. In the immunocompromised host, dis• The free-living female worm is 1 mm long; the adult semination of worms beyond the GI tract produces the male worm is slightly shorter. life-threatening "hyperinfection syndrome. "296.297 The presence of a persistent carrier state greatly enlarges the 7.2. Epidemiology at-risk population for severe disease during periods of immune suppression. Strongyloides is an unusual parasite in that the hu• man is the major host, although some other animals, 7.1. The Organism including cats, dogs, and subhuman primates, may har• bor active infections. The frequency of infection of these Strongyloides stercoralis is a nematode that com• animals in endemic areas is not known. The parasite is pletes its complex life cycle within the human host. 295 found worldwide and is most common in the tropics and The infective form is the filariform larvae that live in soil sUbtropics. Approximately I % of dogs in the eastern contaminated with feces and penetrate exposed skin United States may be infected. Patients may have no areas that come into contact with the soil. These larvae history of travel to an endemic region. Chronic stron• follow the venous circulation to the right heart and to the gyloidiasis is a condition of relatively low worm burden pulmonary alveolar capillary bed (Fig. 12). The worms restricted to an autoinfectious cycle between the skin and then penetrate into the alveolar space, are carried up the the intestinal tract, but without a sufficient immune re• bronchial tree, and are swallowed. Some larvae migrate sponse to clear the infection. Chronic infection has per• through other tissues, especially muscles, producing lo• sisted for over 30 years in some patients. cal symptoms. In the small intestine, the larvae mature The exact components of the immune system re• through two molts, producing adult female worms that sponsible for prevention of disease or the reduction of produce fertilized eggs through parthenogenesis. This the severity of infection are not known. 295 Disseminated process occurs within the intestinal mucosa, where eggs infection has been reported in people with a broad array mature to first-stage rhabditiform larvae. Maturation of of immune defects. 298 This population includes individu• the rhabditiform larvae occurs over 24-48 hr. These lar• als with hematopoietic malignancies or connective tissue vae are passed in the stool or enter an autoinfective cycle disease being treated with immunosuppressive therapies within the GI tract. The autoinfective reproductive cycle (notably corticosteroids); hosts with congenital or ac• within the GI tract allows for enhanced growth in the quired hypogammaglobulinemia, chronic malignancies, absence of immunologic controls. Some of the rhab• malnutrition, severe bums, or alcoholism with hepatic ditiform larvae mature within the intestinal lumen and cirrhosis; and persons with occupational exposure to penetrate into the vascular tree via the wall of the bowel contaminated feces. 299-306 Increased corticosteroid dos• or perianal skin (external autoinfection) to reinitiate the ages used for the treatment of Strongyloides-induced cycle. Larvae passed with the stool may become infec• bronchospasm or for organ graft rejection have been as• tive either via direct maturation or via intermediate sexu• sociated with the development of disseminated infec• al development into male and female forms. The fil• tion.307-312 Abdominal surgery or steroid therapy for ariform larva is approximately 600 fLm long, while the apparent ulcer disease, ulcerative colitis, or Crohn's dis• rhabditiform larva is approximately 200-300 fLm long. ease can exacerbate underlying infections. 309 ,313,314 The hyperinfection syndrome has also been reported in nor• mal individuals without apparent predisposing immune defects. Strongyloidiasis has been reported to be more com• mon in sexually active homosexual men with normal immune function. Direct transmission of the parasite oc• curs via rectal intercourse, by oral-anal exposure, or by contact with skin in the perianal area. Few patients with AIDS are reported to have developed disseminated strongyloidiasis.7,302,306 This finding contradicts the per• ception that cellular immunity is solely responsible for protection against Strongyloides. The relative absence of this finding in AIDS may reflect underdiagnosis or unre• ported cases of disease, but it is apparent that this infec• FIGURE 12. Stroll[?v/oides stercora lis larva isolated from the sputum of a patient with disseminated strongyloidiasis due to an ACTH• tion is still more common in other classes of immu• secreting tumor. nocompromised individuals. PNEUMOCYSTIS CARlNlI AND PARASITIC INFECTIONS 313

FIGURE 13. Chest radiograph of a patient with disseminated strongyloidiasis. The patient had fe• ver, hemoptysis, hypoxemia, and gram-negative bacteremia with fluctuating, dense pulmonary infil• trates.

7.3. Pathogenesis formation may occur around degenerating larvae, but is often absent during immune suppression. Bacterial or The role of the immune system in the modulation of fungal infection carried from the lumen of the GI tract infection due to Strongyloides is demonstrated by may cause acute infection of the bowel wall, peritonitis, changes in the course of disease in the presence of im• or sepsis. Involvement of the CNS is common, with mune suppression (Figs. 12 and \3). In the normal host, meningitis due to Strongyloides and to accompanying repenetration of the gut wall by maturing filariform lar• organIsms. vae is limited. Long-standing infection may be associ• ated with minimal fibrosis, with adult worms in the 7.4. The Patient crypts of Lieberkiihn, and with eggs and larvae in the bowel lumen. Chronic infection produces minimal in• Acute GI infection will generally produce epigastric flammation of the bowel wall with some villous blunt• fullness or pain and, in some individuals, diarrhea and ing. With immune suppression, especially in the setting malabsorption.3 15 Passage of larvae through the lungs of corticosteroids, penetration by the larvae through the may produce eosinophilic pneumonia or "Loeffler's syn• gut wall increases. In this setting, worms accumulate in drome" or milder manifestations of dyspnea, cough, the lungs in significant numbers. This penetration pro• bronchospasm, and fever. 316 Most of these individuals duces bowel wall edema with mucosal ulceration and will have a peripheral blood eosinophilia. Gram-negative mucous secretion. Depending on the level of immune septicemia and necrotizing pneumonia may occur numer• suppression, the inflammatory response on the wall of ous times without specific treatment of the underlying both the small and large intestine may be severe or mini• worm infection. Gram-negative meningitis is a common mal. The inflammatory response is both acute and chron• complication of strongyloidiasis; larvae are infrequently ic, and includes plasma cells, eosinophils, histiocytes, detected in the meninges or CSF of affected patients. giant cells, lymphocytes, and neutrophils. Granuloma Bacterial superinfection as a complication of strongy- 314 CHAPTER 10 loidiasis is equally common in nonnal and in immu• observed. Mortality with disseminated infection gener• nocompromised individuals, supporting the presumption ally exceeds 75% and is usually due to gram-negative that bacterial infection is a function of wonn penetration, sepsis. Because the consequences of disseminated rather than of the underlying immunodeficiency state. Strongyloides are so grave, preemptive treatment should The mechanism of such superinfection is unknown, but be considered prior to elective immune suppression in superinfection occurs in one third to one half of individu• patients with exposures to endemic regions, even without als with disseminated infection. identification of organisms. 294 Many individuals with chronic infection are asymp• tomatic. Others have abdominal pain, diarrhea, and ur• ticaria. 301 In chronic infection, respiratory symptoms are 7.6. Diagnosis less prominent; however, immune complex disease may Early diagnosis and therapy are the main detenni• cause arthritis. The two common skin manifestations of nants of outcome. The diagnosis of strongyloidiasis strongyloidiasis include (1) a migratory, pruritic, raised, should be suspected in the presence of GI symptoms linear rash called "creeping eruption" or "larva currens" accompanied by urticaria or eosinophilia or in individu• and (2) crops of urticarial eruptions that appear to be als who have lived in endemic areas. Because systemic manifestations of immediate hypersensitivity reactions to manifestations may be altered by the presence of immu• migrating wonns. Two thirds of individuals with chronic nodeficiency, clinical suspicion in the presence of rhab• infection will develop transient and recurrent urticarial ditiform larvae found in stool or in duodenal aspirates eruptions on the skin of the waist and buttocks. The should be considered sufficient for the diagnosis in the migratory rash may move across the skin at a rate of up appropriate host. Strongyloidiasis needs to be considered to 10 cm/hr. It is unclear whether these eruptions are a in the appropriate patient whose pneumonia does not reaction to the worms themselves, secreted antigens, or respond to therapy based on sputum examination and components of the skin or gut flora that are carried along culture data. GI symptoms are frequently missed because with the organism. Visceral or cutaneous migration ap• of the preeminent pulmonary or CNS symptoms. 3lS Neg• pears to be much slower, but may produce a similar rash. ative stool examinations may be misleading. Eosino• philia is frequently absent in disseminated infections. 7.5. Disseminated Strongyloidiasis: The diagnosis of strongyloidiasis is based on the JJHyperinfection Syndrome" demonstration of filarifonn larvae in stools, sputum, or CSF. In chronic infection, small numbers of larvae may The predilection of this organism tor the lungs and be hard to find. Larvae may be found by use of the for the CNS is manifested most impressively with dis• Enterotest capsule ("string test"), which contains a long seminated infection in immunocompromised individuals nylon thread. The swallowed capsule releases the thread, (Figs. 12 and 13).296,303 The complications associated which is withdrawn after several hours and may be with dissemination reflect both a large wonn burden and coated with mucus containing larvae. Duodenal aspira• the effects of organisms accompanying the migrating tion or purged stool specimens may also reveal organ• nematodes. Local and systemic infections and allergic isms not detected in routine specimens, Sputum exam• responses may be seen to both the worms and the "pas• ination may reveal bacterial or fungal pneumonia in the senger" bacteria from the gut. Unlike the transient eo• absence of identifiable larvae. Diagnosis is occasionally sinophilic pneumonia that may be seen with acute infec• made on unstained wet-mounts of bronchoalveolar lav• tion, the hyperinfection syndrome is accompanied by age specimens or transtracheal aspirates from infected significant pneumonitis. 312 Pulmonary bacterial superin• lungs. 306 Fonnal-ether concentrates of sputum may be fection occurs in the setting of small-airway obstruction of use if the larvae are few in number. The wonn will secondary to entrapped worms. Pneumonitis is generally also be seen by Papanicolau stain or by experienced ob• accompanied by abdominal crisis: severe abdominal pain servers on Gram's and acid-fast stains of concentrated with ileus, small-bowel obstruction, and occasionally, specimens. septic shock. Hepatic failure has been reported; CNS Neither chest nor abdominal radiologic studies are involvement may include eosinophilic meningitis, al• diagnostic of infections. Chest X rays show patchy or tered mental status, coma, or focal neurologic deficits. diffuse bilateral pulmonary infiltrates (Fig. 13). Pulmo• Polymicrobial bloodstream infection may be seen and nary processes may be transient or progress to consolida• includes the entire range of gut flora, including Candida. tion, especially in the presence of bacterial superinfec• Cavitary pUlmonary lesions may develop, and transient tion. These processes clear with appropriate therapy. rashes or skin swelling of the buttocks or lower abdomen Barium swallows demonstrate duodenal and jejunal dila• may be noted. Peripheral blood eosinophilia is variably tations and bowel wall edema with narrowing in areas of PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 315 fibrosis. Disseminated disease is frequently accompanied this admission. He has a history of heavy smoking and alcohol abuse by dilatation of the small bowel with air-fluid levels. and a sister with a history of active pulmonary tuberculosis. During an In the immunologically normal individual with ac• evaluation for hypertension and angina 3 years prior to admission, the patient was noted to have a 5-mm nodule in his left chest on chest X tive infection, higher titers to Strongyloides antigens ray. No further evaluation of this nodule was performed at the time. A have been demonstrated. The utility of these tests in few days prior to admission to Massachusetts General Hospital, he individuals with disseminated infection has not been es• presented to an outside hospital with chest pain, nausea, and vomiting. tablished. Both immunofluorescent assays and ELlS As He was ruled out for myocardial infarction, but was found to have have been described. These assays may become useful in exercise-induced anginal electrocardiographic changes. His laboratory evaluation included the following values: potassium, 1.9; chloride, 89: detecting at-risk populations before the initiation of im• bicarbonate, 49: glucose, 150-180; a fasting cortisol of 72.3 (8 AM) munosuppressive therapy. Antigen detection tests are un• and 56.4 (12 PM). A review of systems revealed: an increase in anxiety, der development. bilateral lower extremity edema, increased abdominal girth with progressive dyspnea on exertion. an increased appetite but a 14-pound weight loss. The patient had new-onset diarrhea without abdominal 7.7. Therapy pain and a cough with occasional hemoptysis but with little sputum production. He did note intermittent fevers as high as 101°F and pe• All patients infected with S. stercoralis should be nile paresthesias when urinating. He was allergic (hives) to sulfa treated. Uncomplicated GI infections may be treated suc• drugs. cessfully with thiabendazole, 50 mg/kg per day (PO), On physical examination, the patient was a Hispanic man who divided into two doses, to a maximum dose of 3 g/day appeared cushingoid in body habitus. His skin examination revealed over 2 or 3 days. Thiabendazole has many toxicities, hyperpigmented knuckles and nail beds. He had three-plus pitting edema to the knees without clubbing. His chest X ray (Fig. 13) re• including nausea, vomiting, dizziness, and, occasion• vealed a right middle lobe infiltrate with mediastinal widening and a ally, a sense of disembodiment and of urine odor. In generalized interstitial pattern. His oral examination revealed thrush. uncomplicated disease, lower doses are likely to be ef• His white blood count was normal without eosinophils. His ACTH fective, and confirmation of the clearance of worms was 665 (normal range 10-56). His amylase was 269 (45-113); his should be made by stool examination at 6 and 12 months ionized calcium was 0.94 (1.14-1.30). Stool examination was negative for pathogenic bacteria or parasites. Sputum examination and cultures after therapy. Disseminated disease is treated with the were unremarkable. same drug for a period of 5 days. A number of drugs are The patient developed progressive respiratory distress requiring being studied, but are of less certain efficacy, including intubation and transfer to the medical intensive care unit. Deep• mebendazole, cambendazole, and albendazole in high suctioned sputum examination was positive for both P. carinii and S. doses. Ivermectin has proven useful and less toxic and is stercora lis (Fig. 12). He was treated with thiabendazole, intravenous pentamidine, and broad-spectrum antibiotics. His admission blood cul• in clinical trials. 3l7 Of interest, the immunosuppressive tures grew enteric gram-negative rods overnight, and sputum cultures agent cyclosporin A may have some efficacy in the treat• grew CMY. The patient failed to clear his Strongyloides infection ment of strongyloidiasis. However, we have seen stron• with thiabendazole and was treated with ivermectin. Nonetheless, he gyloidiasis in organ transplant recipients receiving cyclo• progressed to perforation of his bowel. Liver biopsy during laparo• sporin A to prevent graft rejection. tomy revealed a malignant small cell neoplasm consistent with small cell carcinoma of the lung. The patient expired on the 14th hospital Patients at risk for dissemination due to immune day. suppression should be evaluated for the presence of the Comments. This case demonstrates the importance of a careful carriage state. Patients with disseminated infection are epidemiologic history in the management of the immunocompromised treated for 5-7 days for strongyloidiasis, but may require patient. Patients from areas endemic for S. stercoralis remain at risk for more prolonged therapy for secondary bacterial infec• disseminated infection ("hyperinfection") for many years after the ini• tial exposure. This common presentation included a negative stool tions of the lungs, eNS, or abdomen. Immunosuppres• examination for S. stercoral is and a normal sputum Gram's stain. The sive agents should be reduced as much as possible and patient was immunocompromised due to an ACTH-secreting small cell areas of focal infection drained. Repeated courses of carcinoma presumed to be lung-derived. Pulmonary infection with therapy may be necessary in chronically immunosup• Strongyloides is probably less important than the frequency of bron• pressed individuals (i.e., those with AIDS or organ chial obstruction with subsequent bacterial superinfection. The cata• clysmic event in this patient's course was bowel perforation and gram• transplants). Therapeutic failures with thiabendazole negative sepsis despite appropriate antibiotic therapy. Sustained bacte• may be successfully treated with ivermectin. Side effects remia even without perforation is a common complication of stron• of therapy may include hypotension, neurotoxicity, and gyloidiasis in the compromised host. Patients may have paralytic ileus leukopenia with mild elevations of liver function tests. with or without perforation, hemorrhagic and fluctuating pulmonary infiltrates progressing to adult respiratory distress syndrome, bacte• remia or bacterial pneumonia, and parasitic or bacterial meningitis or both. While eosinophilia (>25-30%) is common, this finding is usu• Illustrative Case 3 ally absent in patients receiving corticosteroids. Larvae are detected in sputum or pulmonary aspirates, especially when concentrated prior to The patient is a 66-year-old man who immigrated to the United examination. States from the Dominican Republic approximately 30 years prior to In patients known to be at risk for Strongyloides infection, aggres- 316 CHAPTER 10 sive evaluation or preemplive therapy is mandatory prior to initiating 8.2. Life Cycle immunosuppression-e.g., organ transplantation or chemotherapy. Larvae have been detected in purged stools when routine examinations The life cycle of the organism begins with the in• are unremarkable. gestion of food contaminated by infective cysts. Excyst• The presence of P. carinii and of CMV is of uncertain signifi• ment releases motile trophozoites covered with filopodia cance. These pathogens speak to the chronicity of immune suppression and the role of corticosteroid excess in the pathogenesis of this patient's used for epithelial attachment. The organism grows in a illness. low-oxygen environment. Invasive trophozoites in tis• sues are large (20-40 f.Lm) in comparison to those found in carriers (10-25 f.Lm). The characteristic of hema• 8. Entamoeba histolytica tophagia is considered diagnostic of invasive amebae and active disease. The nonpathogenic cysts of E. hartmanni Entamoeba histolytica is a parasite of worldwide are much smaller in diameter (10 f.Lm) than those from E. distribution that lives in the intestinal lumen of over 500 histolytica (8-20 f.Lm). Humans are definitive hosts for million people.3ls The organism is usually a benign E. histolytica. The development of good animal models commensal. Under appropriate conditions, E. histolytica has been difficult.320 However, characteristic intestinal invades the intestinal mucosa, causing dysentery, mass and hepatic disease has been produced by coinfection lesions (ameboma), or extraintestinal lesions including using pathogenic E. histolytica with bacteria and by di• liver abscesses. Because the basis of the conversion from rect inoculation of organisms into the hepatic par• commensal to invasive parasite is unclear, the mecha• enchyma or circulation.320.32l nism by which amebiasis is exacerbated by immune sup• pression is also not understood. The significant clinical 8.3. Epidemiology features of amebiasis are the separation of nonpathogenic from pathogenic amebae, the distinction of lumenal in• Infection due to E. histolytica is common in tropical fection from invasive disease, and the consideration of regions, in parts of Central and South America, India, this diagnosis in the setting of a patient with GI symp• and western and South Africa. Up to 50% of the resi• toms prior to the elective initiation of immunosuppres• dents of some areas are infected. People in these hy• sive therapy. perendemic regions are subject to constant reinfection. Occasional epidemics of amebiasis are related to con• 8.1. The Organism tamination of a water supply or to unsanitary conditions surrounding institutionalized individuals. Serologic as• Human amebae include several species of parasites: says are useful for the detection of invasive disease. E. histolytica, E. hartmanni, and E. gingivalis. Rarely, These tests generally revert to negative within 6-12 amebae common in animals have been found in humans; months after the acute invasive disease. However, the these organisms have not been implicated in disease. The indirect hemagglutination assay remains positive for motile fonn of the organism is the trophozoite, which years. Invasive disease is more common in persons of lives in the colonic lumen. The trophozoites divide and lower socioeconomic condition. Amebiasis is the third encyst, producing thick-walled cysts with four nuclei. leading cause of mortality due to parasitic infection, fol• Unlike other parasites, these cysts do not persist in tis• lowing malaria and schistosomiasis. sues and are found only in the lumen of the human bow• Male homosexuals in the United States have a fixed el. Trophozoites are fragile and have not been implicated high incidence of carriage of E. histolytica, with some in the transmission of disease. Trophozoites are found in urban areas reporting infection rates approaching 30% of tissues during invasion. Strain differences appear to be sexually active individuals. 322 ,323 The incidence of inva• common in E. histolytica. These differences account for sive disease has not corresponded to the presence of geographic variation in the pathogenicity of the organ• luminal infection in homosexual AIDS patients in either ism. There are antigenic and enzymatic differences the United States or Latin America. Reports of the in• between pathogenic and nonpathogenic strains of E. his• creased incidence of amebiasis in homosexual patients tolytica. Characteristic electrophoretic patterns of isoen• with AIDS in the United States do not demonstrate an zymes or "zymodemes" may distinguish pathogenic increased prevalence of pathogenic strains or of invasive strains. 3l9 /n vitro, it has been possible to change a non• GI disease,7,324 It appears that most of the parasites re• pathogenic organism into a pathogenic organism by al• covered from homosexual men are nonpathogenic and tering the bacterial flora surrounding the organisms in are probably not relevant to GI symptoms. AIDS patients culture. It is not clear that this conversion occurs in vivo. do not appear to be at increased risk for the development The determinants of pathogenicity are not clear. of amebiasis. By contrast, immunocompromised patients PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 317 recelvmg chemotherapy, corticosteroid therapy, or im• formation. Progressive necrosis and parenchymal reac• munosuppression surrounding organ transplantation are tion provide a thin capsule to the enlarging amebic ab• at a greater risk for the development of fulminant co• scess. Organisms are found primarily at the edge of the litis.325.326 abscess. Amebic abscesses are single lesions in over 80% of individuals and are generally found in the right 8.4. Immunology lobe in the posterior portion adjacent to the diaphragm. Large abscesses may decompress into the right or left Antibodies against E. histolytica that develop dur• chest or into the bronchial tree, producing catastrophic ing acute infection do not appear to be protective. 327 .328 disease. The necrotic debris has been characterized as The presence of serum antibodies correlates with the "anchovy paste" exudate, which may be found in the presence of both invasive amebiasis and hepatic disease. sputum after rupture of an abscess into the bronchi. Rup• Antibody can lyse trophozoites in vitro. Complement can ture of abscesses of the left lobe of the liver may be also produce partial lysis. Complement-resistant amebae associated with acute pericardial tamponade. Bacterial may "cap-off" bound surface antibody or may shed sur• superinfection is surprisingly uncommon. With appro• face antigens to limit the efficacy of the humoral immune priate therapy, pathologic changes in the intestines or the response. The cellular immune response appears to be liver resolve without fibrosis. depressed acutely during infection and returns after treat• ment of disease.326.327 Resistance to subsequent infec• 8.6. The Patient tion appears to be mediated by the cellular immune re• sponse. The absence of an increased incidence of The presentation of amebic infection depends on the invasive disease in patients with AIDS suggests that oth• extent of disease and the condition of the host. Clinical er mechanisms are also operative. This absence is partic• presentations of this common disease can be divided into ularly notable given the increased carriage of amebae by subcategories: asymptomatic cyst carriers; a possible male homosexuals. chronic, nondysenteric colitis syndrome; acute rec• tocolitis; toxic megacolon with fulminant colitis; am• 8.5. Pathogenesis eboma; and painless rectal bleeding. The interaction of immune depression with the presentation of disease ap• The pathology of amebic disease is important. The pears to determine the severity and rapidity of disease characteristics of inflammatory changes in the bowel progression. 326 Immunocompromise does not appear to may easily be confused with other more benign pro• alter the differentiation between invasive and noninva• cesses. Invasion of the intestinal mucosa produces a lo• sive disease. Since local inflammation is usually modest, cal loss of mucin from the surface of epithelial cells, fibrosis is not characteristic of disease. The alterations with underlying edema and hyperemia. Superficial ul• produced by immune suppression may be subtle. It ceration develops with minimal local inflammation. Ul• should be anticipated that bacterial superinfection and ceration progresses superficially, with penetration into peritonitis are more common in the setting of broad• the mucosa producing the characteristic "flask ulcer" ex• spectrum immune suppression such as with corticoste• tending into the submucosa of the intestinal wall. The roid therapy. The important factors in infection are the ulcers themselves are usually small with raised borders strain of E. histolytica and the nutritional status of the and a necrotic base and with normal mucosa between host. adjacent ulcers. Extensive disease may involve large seg• Only 10-20% of individuals infected with E. histo• ments of the intestinal mucosa. Organisms are found lytica will develop clinically significant disease. Most superficially at the edge of the epithelial lesion. Chronic individuals will spontaneously eradicate the parasites. amebic infection will result in thickening of the colonic Symptomatic individuals are at risk of further complica• mucosa. Progressive disease within the wall of the intes• tions of disease if not adequately treated. It is possible tine can produce a pseudotumor consisting of necrotic that the majority of these infections are with non• tissue with acute and chronic inflammation and granula• pathogenic strains. A syndrome of irritable bowel dis• tion and fibrosis. This mass lesion is called an ameboma. ease in the presence of E. histolytica has been termed Further complications occur locally with perfora• chronic nondysenteric infection. There is some contro• tion of the GI tract or by penetration into the portal versy as to whether or not the organisms playa signifi• circulation, allowing seeding of the liver. 319 Liver in• cant role in the development of the syndrome of chronic volvement may occur in the absence of clinically impor• intermittent abdominal pain with diarrhea. 329 The basis tant intestinal disease. The liver is involved by local of this pattern of infection remains unclear. In general, inflammation, followed by focal necrosis and granuloma the presentation of acute disease depends on the extent of 318 CHAPTER 10 colonic involvement and the rapidity with which the dis• demonstrated in only 38% of individuals with hepatic ease develops. "Acute rectocolitis" usually involves the abscess. The clinical presentation is usually acute, with gradual onset of diarrhea and acute abdominal pain. Wa• abdominal pain, fever, and symptoms localizing in the tery stools may become blood-stained. Tenesmus is com• subdiaphragmatic region. Right shoulder pain is com• mon. Many small, superficial, mucosal ulcerations with mon and is increased by coughing. Fever, rigors, and segmental distribution are seen by colonoscopy. The ul• sweats are common, associated with cachexia. Some pa• cers contain necrotic debris and trophozoites, with un• tients will present with a more gradual evolution with derlying hyperemia and some submucosal hemorrhage. hepatomegaly and anemia. In most individuals, liver Fecal leukocytes are uncommon. While adults are gener• function tests are mildly abnormal, and the patients may ally well compensated, children may be toxic, with high be slightly jaundiced. The patient will often have an fevers, and become rapidly dehydrated. 330 Right lower elevated white blood count. Other extraintestinal foci of quadrant pain may be due to acute appendicitis (which is infection may include the skin of the perianal region or uncommon) or to "typhlitis," which usually occurs in the the skin or tissues overlying the involved intestines or presence of mucosal thickening in the ileocecal region. thoracic regions. Complications are common in individuals developing amebic appendicitis. Liver abscesses, bleeding, and per• 8.7. Diagnosis foration with fistula formation are common complica• tions in patients with undiagnosed amebic appendicitis. The diagnosis of amebiasis is made by the demon• Host factors seem to determine the progression of stration of trophozoites of E. histolytica in smears made acute dysenteric disease to the fulminant colitis. 326.327 from colonic samples. Motile organisms containing red Fulminant colitis is a rapidly progressive syndrome. The blood cells in the presence of small superficial ulcers of patient may present with bloody diarrhea with foul odor the colonic mucosa are the most common findings. Dif• and diffuse abdominal pain. High fever is present, with ferentiation of pathogenic amebae from nonpathogenic signs of ileus, dehydration, and shock developing early. organisms can be done on wet-mounted smears using Tenesmus and rectal bleeding are present, and perfora• fresh or preserved specimens. The addition of iodine will tion with peritonitis occurs in up to two thirds of these allow the differentiation of E. histolytica cysts from individuals. Toxic megacolon may occur, but is uncom• yeasts and other amebic species. The addition of methy• mon. Extraintestinal disease may occur. The syndrome is lene blue will allow the differentiation of cysts from more common in the presence of malnutrition, in older leukocytes, which stain blue. Areas with both mucus and individuals, and in the immunocompromised patient, blood are optimal for examination. Cyst morphology is particularly those receiving corticosteroids. Up to two best seen on fixed specimens stained with iron~ thirds of these individuals will die due to complications hematoxylin or a trichrome stain. This morphology is of intestinal injury. Surgical debridement is of uncertain more easily observed after concentration of a specimen value in the absence of acute peritonitis or toxic mega• using sedimentation or flotation on formalin~ethyl ace• colon. Both antiamebic and antibacterial therapies are tate. necessary. Serologic diagnosis is useful for the diagnosis of Up to 2% of patients with invasive disease will invasive GI disease or hepatic disease, but is rarely use• develop ameboma, usually of the cecum or ascending ful acutely. Radiologic evaluation will reveal the pres• colon. The diagnosis is frequently incidental to the eval• ence of thickened intestinal walls in severe amebic col• uation of acute dysenteric amebiasis or with an asymp• itis, with narrowing and loss of folds. 331 Free air may be tomatic abdominal mass lesion. Diffuse thickening of the observed in the presence of perforation. gastric wall with mucosal ulceration may give the ap• In the absence of localizing signs, the diagnosis of a pearance of Crohn's disease. Treatment of this complica• liver abscess may be overlooked. Ultrasonography, CT, tion with corticosteroids may have disastrous side ef• or liver~spleen scintigraphy will demonstrate liver ab• fects.325 The presence of rectal bleeding without pain scesses in the majority of cases. The presence of a liver may be chronic and is a reflection of congestive colitis, abscess with a positive amebic serology should be con• usually without ulceration. sidered diagnostic of amebic liver abscess. In immu• Extraintestinal disease is generally restricted to nosuppressed individuals or in malnourished patients amebic liver abscess. This complication is more com• with chronic abscesses, negative serologies may be slow mon in lower socieconomic groups, in men than in wom• to convert to positive. Organisms are infrequently found en, and in alcoholics than in nondrinkers. In addition to on stool examination to confirm the presence of E. histo• poor hygiene, host immunity may also be a contributing lytica infection. Serologic tests are particularly useful factor. Amebic liver abscess usually occurs in the ab• because they peak 2~3 months after acute infection and sence of acute rectocolitis. Intestinal involvement can be generally return to low levels by I year after infection. In PNEUMOCYSTIS CAR/Nil AND PARASITIC INFECTIONS 319

TABLE 9. Drugs for the Treatment of Amebiasis

Clinical presentation Drug Adult dosage"

Asymptomatic cyst passer Drug of choice lodoquinol h 650 mg tid x 20 days Alternatives Diloxanide furoate' 500 mg tid x 10 days Paromomycin 25-30 mg/kg/day in 3 doses for 7 days

Invasive intestinal disease Drugs of choice Metronidazole'" 750 mg tid x 10 days followed bv iodoquinol or As above diloxanidc As above

Alternatives Dehydroemetined 1-1.5 mg/kg/day (max 90 mg/day 1M for followed by up to 5 days) iodoquinol As above

Hepatic abscess Drugs of choice Metronidazole As above follDlved bv iodoquinol As above

Alternatives Dehydroemetine As above followed by chloroquine phosphate 600 mg base (l g)/day x 2 days, then 300 mg base (500 mg/day x 2-3 weeks) plus iodoquinol As above apediatnc doses are different. "Maximum dosage of 2 g/day should flol be exceeded (risk of optic neuritis), cPossible carcinogen; not for use in pregnant women; other nitroimidazoles available outside the United States (tinidazole. ornidazole) may be preferred. dMonitor EKG; probably preferred over emetine (1 mg/kg per day 1M x 5 days; maximum 60 mg/day),

endemic areas, positive serologic tests are less useful. men; they include metronidazole and the nitroimidazole Percutaneous drainage of a large abscess carries the risk derivatives (tinidazole, omidiazole, secnidazole, and of rupture and spread of infection. However, per• nimorazole ). cutaneous drainage in the setting of disease unresponsive Treatment for asymptomatic cyst passers is contro• to antibiotics or of anticipated rupture or in the presence versial due to the frequency of infection with non• of mixed bacterial and amebic infection may be indi• pathogenic strains of amebae. 329 Some recommended cated. Occasionally, percutanous drainage has provided treatments are presented in Table 9. The luminal agents a diagnosis in the setting of negative serologic tests. such as diloxanide are more effective than metronidazole Catheters placed into liver abscesses should be removed in the absence of invasive disease. Invasive disease immediately after draining the lesion. should be treated with a nitroimidazole with a luminal agent. In the presence of colonic perforation, antibac• S.S. Therapy terial therapy should be added, using metronidazole to cover anaerobic flora as well as the amebic infection. A broad range of antiamebic drugs are available, The need for surgery with microperforation is controver• and their use is based both on their site of action (tissue sial. However, with acute appendicitis or toxic mega• vs. colonic lumen) and the potential toxicities of each colon, surgery will be necessary. Ameboma may be agent (Table 9). Emetine and dehydroemetine must be cured with antibiotic therapy alone. 332 Similarly, liver given intramuscularly and have depressant effects on the abscess is rarely an indication for surgery. Antibiotic myocardium. These agents are effective in tissues. therapy is generally successful, and abscesses resolve Agents with actions within the lumen of the bowel in• without fibrosis. Because treatment failures with metro• clude diiodohydroxyquine, diloxanide furoate, and par• nidazole have been observed, liver abscesses are gener• omomycin. The most effective drugs available at present ally treated with combination therapy using a nitro• have activity both in the tissue and in the intestinal lu- imidazole agent and dehydroemetine. 320 CHAPTER 10

9. Primary Amebic Meningoencephalitis primarily polynuclear leukocytes. As Naegleria invades the superficial cortex, the olfactory and frontotemporal Primary amebic meningoencephalitis (PAM) is an areas of the brain quickly develop hemorrhagic necrosis. uncommon infection of the CNS produced by the ame• Trophozoites are prominent. bae Naegleria and Acanthamoeba. 333 Depending on the The pace of infection with Acanthamoeba is gener• species of organism, the progression of disease may be ally slower, producing ultimately fatal disease in 2-3 chronic or acute. PAM is usually fatal. weeks. The inflammatory response is usually lymphocy• tic, with macrophages, granuloma formation, giant cells, 9.1. The Organism and vasculitis. The pathology and clinical picture are those of multiple space-occupying brain abscesses. While secondary involvement of the nervous system These abscesses are located in the white matter in deep with amebic infection can occur with Entamoebae histo• midline and midbrain structures. Organisms are found in lytica, primary infections are due to Naegleria fowleri tissues, but, in general, not in CSF. Because no therapy and a number of species of Acanthamoeba. Naegleria is available, this infection is uniformly fatal. Because of trophozoites are amorphous or sluglike in shape. The the effects on deep structures, Acanthamoeba may cause most easily identifiable form of the organism is the fla• a picture of subacute or chronic encephalitis before focal gellate induced from trophozoites placed in distilled wa• deficits develop related to brain abscesses. ter. Flagellates do not occur during human infection. Acanthamoeba trophozoites have pseudopodia surround• 9.4. The Patient and Diagnosis ing one end. Both Naegleria and Acanthamoeba may be seen containing ingested red blood cells; both occur in a While acute PAM will present as severe bacterial thick-walled cyst form. The trophozoites of these organ• meningitis, the patient will rapidly progress from head• isms vary from 7 to 20 ILm in size. These organisms are ache, fever, and vomiting to seizures, coma, or paraly• capable of producing PAM in many animal species by sis. Naegleria may produce false sensations of taste or intranasal or intravenous inoculation. There does not ap• smell similar to those seen in some patients with heart pear to be an intermediate host. The virulence of a given failure and early brainstem herniation. Naegleria tro• strain will depend on the organism and on the host's phozoites will be found in CSF, with markedly low glu• immune status. cose levels and a neutrophil count as high as 15,000. The CSF protein level may be normal or slightly elevated. 9.2. Epidemiology Progression is even more rapid in immunocompromised hosts. Amebic meningoencephalitis has been reported Patients with Acanthamoeba infection may also pre• worldwide. The majority of cases are due to Naegleria sent with headache and fever. Focal neurologic deficits species. The natural habitat of these amebae is soil and or seizures occur early in the course of this subacute fresh warm water. Common-source epidemics have been disease. The patient will undergo a gradual neurologic detected as a result of contaminated water supplies. deterioration over the course of 2-4 weeks. The clinical However, these organisms are commonly found in pools picture exceeds what would be expected from a focal of warm water such as aquariums or hospital hydro• brain abscess. The CSF generally does not contain or• therapy tanks. Reported cases of PAM have come from ganisms, and the glucose is normal or slightly depressed. throughout the United States and Europe, central Africa, The CSF contains 100-400 cells, which include both India and other parts of Asia, and Australia. Pathogenic lymphocytes and neutrophils. Organisms are found in organisms are easily missed in the evaluation of acutely brain biopsy specimens. Serologic tests are useful diag• ill patients. nostically, but not clinically. Acanthamoeba infection may produce disease of the eye or respiratory tract in 9.3. Pathogenesis normal hosts. Eye injury has been associated with infec• tions carried by contact lenses or local trauma. Naegleria generally enters the CNS via the olfac• tory neuroepithelium when water or dust particles enter 9.5. Therapy the nose. By contrast, Acanthamoeba causes infection of other organ systems, including skin, lung, or eye, and Few individuals have survived primary amebic then spreads to the CNS via the bloodstream. The clini• meningoencephalitis.333.334 Amphotericin B should be cal presentation of Naegleria infection is an acute and used at a dose of at least I mg/kg per day. Given the rapidly progressive meningitis that is fatal in less than 4 rapid progression of PAM, there is no opportunity for days without therapy. The inflammatory cell response is gradual escalation of dosing. There is no useful therapy PNEUMOCYSTIS CAR/NIl AND PARASITIC INFECTIONS 321 for Acanthamoeba, although in vitro sensitivity of Acan• United States are acquired outside the country. The exact thamoeba to polymixin, pentamidine, ketoconazole, frequency of these infections is unclear, because the 5-f1uorocytosine, and paromomycin has been demon• pathogen has caused disease as late as 30 years after the strated. initial infection. Distant exposure must be excluded be• fore the diagnosis is excluded. In endemic areas, the annual incidence is 0.1-1 % and may go as high as 5% 10. Leishmaniasis during epidemics. Malnourished or immunocompro• mised individuals are most susceptible to symptomatic Leishmaniasis encompasses a variety of diseases, and severe infections. 336 including cutaneous, mucocutaneous, and visceral dis• Malnutrition is probably the most important immu• ease, depending on the species of Leishmania and the nosuppressive mechanism predisposing to severe vis• immune status of the host. Because all species of ceralleishmaniasis.335.337.338 While many individuals in Leishmania are intracellular parasites of macrophages, endemic areas are infected but develop relatively mild the functional status of T lymphocytes and of cytokines disease, individuals with malnutrition are much more affecting macrophage function will determine whether or likely to develop classic, advanced, visceral disease. not the organism disseminates locally or systemically. This difference is most easily seen in children, in whom untreated symptomatic infection will be fatal in 75-90% 10.1. The Organism of those affected. Only 10-20% of affected individuals will develop clinically apparent disease. 339 In immu• Species of Leishmania can be separated by geo• nosuppressed individuals with hemotologic malignan• graphic distribution and the clinical manifestations of cies, organ transplants, or immunosuppressive therapies, infection. The organisms that cause cutaneous and mu• especially corticosteroids, disease may have a more rapid cocutaneous leishmaniasis include L. braziliensis, L. progression and be more difficult to diagnose. 336 ,340-345 major, L. mexicana, L. tropica, L. peruviana, and L. In these individuals, the disease is more often chronic aethiopica. Leishmania tropica can also cause chronic, and the response to therapy less rewarding, Chronic, relapsing cutaneous disease (recidivans form). Leishma• relapsing, visceral leishmaniasis has been described as a nia donovani, L. infantum, and L. chagasi can cause complication of AIDS in patients from Spain, France, visceral leishmaniasis. Consensus about species differen• and Italy. 346,347 AIDS patients do not develop antibodies tiation will probably result from sequence and hybridiza• to Leishmania, in contrast to the nearly uniform detec• tion analysis using kinetoplast DNA probes. tion of antibodies in immunocompetent individuals and Leishmania exists in two forms. Within the sand fly in non-AIDS immunocompromised patients with vis• vector or in culture, they are single-celled, flagellated ceral disease. It is possible that Leishmania may reduce extracellular promastigotes. Within the cells of verte• immune responsiveness to infections due to other organ• brate hosts, they are amastigotes without f1agellae, 2-3 isms. Antibodies against a broad range of antigens have fLm in diameter. Human infection is initiated by the bite been observed in early visceral disease. of an infected female phlebotomine sand fly. Organisms are phagocytosed by macrophages at the site of the bite 10.3. Pathogenesis and replicate by binary fission within the macrophage. Each strain of Leishmania has a unique and complex Cutaneous and mucocutaneous forms of leishma• interaction with the phagolysosome; in general, the para• niasis begin when promastigotes are injected subcutane• site is resistant to the lysosomal acidic pH. ously by the sand fly and enter local host cells. Local inflammation is primarily lymphocytic and granuloma• 10.2. Epidemiology tous, with necrosis of the skin occurring early. Organ• isms spread via the bloodstream or lymphatics to the The spread of leishmaniasis is dependent on the mucosal surfaces of the nose, mouth, pharynx, and lar• presence of the appropriate species of sand fI y. 335 Other ynx. Inflammation is generally modest. Dermal necrosis than L. donovani and L. tropica, the organism is gener• is probably due to the local immune reaction. Subse• ally maintained in wild animals, including rodents, dogs, quently, hyperkeratosis and acanthosis may occur. The marsupials, and other wild animals. Leishmania don• number of organisms in infected cells is variable. ovani and L. tropica appear to be able to use the human In visceral leishmaniasis, infected macrophages as a definitive host. Various forms of Leishmania are from the skin serve as a reservoir for organisms that found in the southern United States, Central and South infect spleen, lymph nodes, liver, bone marrow, and in• America, and throughout Africa, southern Asia, Europe, testinal mucosa. This infection causes hyperplasia of fo• and the Middle East. Virtually all the cases seen in the cal lymphoid tissue with granulomata. Ulceration of mu- 322 CHAPTER 10 cosal surfaces may occur, and endothelial proliferation rounding tissues. This inflammation is frequently com• may occur in pulmonary alveolar capillaries and in blood plicated by bacterial superinfection. vessels of the renal glomeruli. The spleen and liver are Uncommon forms of leishmaniasis include a chron• enlarged due to parasitization of macrophages and ic relapsing or recidivans disease and DCL. Chronic re• Kupffer cells. Some areas of skin around the initial bite lapsing disease occurs in or surrounding the area of origi• will have nodules containing parasites; some areas that nal cutaneous involvement. Diffuse cutaneous disease is appear normal will also contain parasites. associated with lack of immune reactivity to leishmanial antigens. Patients develop nonulcerative nodules across the skin, with little inflammatory reaction. Visceral 10.4. Immunology leishmaniasis will become symptomatic weeks to months after infection, with the gradual onset of fever, sweats, Immunity to Leishmania is thought to be mediated and weight loss. Nonspecific abdominal complaints ac• by CD4+ T lymphocytes, with lymphokines from these company hepatosplenomegaly and wasting of large mus• cells enhancing the killing of intracellular organ• cle groups. Complications are the results of anemia, isms.347-349 The manifestations of the disease are deter• thrombocytopenia, liver failure, or secondary bacterial mined by the level of immune response. In cutaneous infection. leishmaniasis, patients lacking immune responsiveness to the parasite may develop diffuse cutaneous leishma• niasis (DCL) with little lymphocyte infiltration of areas 10.6. Diagnosis and Therapy of involvement. By contrast, "leishmaniasis recidivans" Patients with symptoms of leishmaniasis are modest is the result of an exuberant lymphocytic response to low problems in differential diagnosis. The cutaneous le• numbers of parasites that persist within macrophages. In sions, especially in the immunocompromised host, visceral leishmaniasis, the host is completely lacking a might be seen in diseases due to mycobacteria, including cellular immune response to leishmanial antigens. 35o M. leprae or M. marinum, cutaneous diphtheria, sar• Parasitization of the reticuloendothelial system is uncon• coidosis, histoplasmosis, yaws, and fungi including trolled. Despite high levels of circulating antibodies in sporotrichosis. Mucocutaneous disease may be confused immune complexes, disease may spread rapidly without with the destructive lesions of lethal midline granu• therapy. Suppressor lymphocytes appear to playa role in lomatous disease or blastomycosis. Visceral leishmania• the loss of antigen reactivity seen in visceral leishma• sis with hepatosplenomegaly can mimic or complicate niasis. lymphoma, malaria, schistosomiasis, endocarditis, bru• cellosis, leukemia, immunosuppression for organ trans• 10.5. The Patient: Clinical Manifestations plantation or with corticosteroids, or advanced histo• plasmosis. 345 .346 Cutaneous and mucocutaneous leishmaniasis may Diagnosis is based on the identification of organ• cause clinical symptoms weeks to years after initial in• isms from tissues. In cutaneous disease, needle aspira• fection. In cutaneous disease, a small papule at the site tion or punch biopsy should be performed at the edge of of the bite will develop into a nodule. Necrosis leaves a the lesion. In visceral kala-azar, tissue aspirate from painless ulcer with raised firm edges. Multiple lesions spleen, bone marrow, lymph node, or liver are often may occur in the same area or along lymphatics. These diagnostic. Parasites are occasionally seen in peripheral lesions will generally heal spontaneously. Specific blood smears. Parasites can be cultured in special media strains of Leishmania may involve the ears, upper face, or in animals. Serologic tests are useful in non-AIDS and nose or cause painful lesions. Immune suppression patients, but may be negative in the first week to 10 days may cause a relapse in previously healed areas. Experi• after infection. 351 ence with leishmaniasis in soldiers serving in the Middle Leishmaniasis is treated wtih pentavalent antimony: East suggests that systemic manifestations of cutaneous stibogluconate sodium (Pentostam) or meglumine anti• disease are common and may reflect organisms found in moniate (Glucantime). Stibogluconate is used at a dose the bone marrow and in other visceral locations in the of 20 mg/kg body weight for 2-3 weeks. Controversy immunologically normal host. exists as to the maximum daily dose, but it should gener• Mucocutaneous leishmaniasis ("espundia") is usu• ally not exceed 850 mg to 1 g daily in adults. Relapse ally a complication of cutaneous disease occurring years with mucocutaneous and visceral disease is not uncom• after the initial skin lesions have healed. Organisms that mon and may necessitate mUltiple courses of treatment spread to mucosal tissues may produce symptoms similar for cure. Occasional abnormalities in liver function tests to sinusitis or nosebleeds. Granulomatous inflammation and EKGs may be seen, with elevations of the total white with necrosis may destroy the nasal septum and sur- blood count as side effects of therapy. Patients may also PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 323 complain of arthralgias. Meglumine is given by injection against giardial infection. 362 Secretory IgA of breast for American cutaneous disease (20 mg/kg per day x 15 milk may also be protective. 363 days). Allopurinol (20 mg/kg per day in 4 divided doses) may have additive efficacy with pentavalent antimony or 11.1.1. Epidemiology in patients with unresponsive disease. Allopurinol mono• therapy may be less toxic, less costly, and more effective Despite the frequency of G. lamblia in the stools of than the antimony compounds. Amphotericin B is anoth• homosexual males, giardiasis is not a common pathogen er alternative for therapy of cutaneous or mucocutaneous of unusual severity in patients with AIDS. 364-367 Giar• leishmaniasis. Pentamidine is an alternative for therapy dia is found in contaminated water, in animals including of visceral disease. Relapses are apparently related to beavers and dogs, and after person-to-person spread in failure to develop an immune response during the course day care centers. 263,354,368-372 Infection rates are high in of therapy. Newer therapies under study include topical institutions for the mentally disabled and in patients with therapies for skin disease and ketoconazole for systemic achlorhydria. The cyst is hardy and survives for months disease due to L. mexicana. 352 in fresh cool water. 373 Small numbers of cysts can cause infection.

11. Other Parasitic Diseases of the 11.1.2. Diagnosis and Therapy Immunocompromised Host Giardia is a common cause of diarrhea and non• The presentations and frequencies of some of the specific abdominal complaints. Unexplained malabsorp• most common parasitic diseases of man are relatively tion or lactose intolerance may be observed. 353,374-376 unchanged in the patient with altered immunity. Others Colonoscopy will be entirely normal. 377 The detection of are important in the presence of specific immune lesions. organisms in stool or on duodenal aspirate or using the The failure to detect enhanced infection may relate to Enterotest vial will provide the diagnosis, Patients are variability in the duration or severity of these diseases in generally treated with metronidazole, 250 mg 3 or 4 normal individuals. More often, the failure of immune times a day for 7-10 days. This drug should be used with suppression to exacerbate infection suggests either a lack caution in children or in pregnant women. Repeat thera• of involvement of the immune system in the control of py may be necessary in up to 20% of individuals. Malab• infection in the normal host or the inability of the organ• sorptive symptoms may be slower to resolve than the ism to complete its life cycle in man. A number of im• infection itself. Alternatively, quinacrine hydrochloride portant infections are occasionally problematic in the pa• can be used for therapy at 100 mg orally 3 times a day for tient with immune dysfunction. These infections are 5 days (2 mg/kg in young children). discussed below. 11.2. Malaria 11.1. Giardia lamblia Given the importance of malaria as a pathogen Giardiasis is the most common protozoan disease in worldwide, it is striking that this intracellular protozoan the United States and an important cause of enteric dis• has not emerged as an opportunistic pathogen in patients ease worldwide. Infection with G. lamblia is caused by with AIDS. The life cycle of malaria begins when the ingestion of food or water contaminated with cysts. Tro• female anopheline mosquito inoculates sporozoites into phozoites develop in the duodenum after exposure of the host during a blood meal. These organisms enter cysts to acid in the stomach. This free-swimming flagel• liver cells and proliferate, releasing merozoites that then late causes disease by attachment to intestinal epithelial invade erythrocytes. Immunity occurs in endemic areas cells and may cause prolonged infection despite therapy. after repeated infection and is both species- and strain• The patient may develop diarrhea, malabsorption, and specific. Passive transfer of antibodies is protective, weight loss of varying degrees. 353 Children are more blocking infection of red blood cells and killing intra• frequently infected than adults, and prior infection ap• cellular organisms via antibody-dependent cellular cyto• pears to confer protection against subsequent attacks. 354 toxicity (ADCC). ADCC requires normal splenic func• Immunocompromised individuals appear to be at greater tion. The development of immunity requires normal risk, perhaps most often related to malnutrition. 355 Infec• T-cell function. Immunity to sporozoites appears to be tion appears to be more common in patients with hypo• mediated at least in part by T cells and not by antibody. gammaglobulinemia or dysgammaglobulinemia, al• Malaria is primarily a tropical disease and is caused though circulating antibody does not appear to be by four major species, with each having different clinical protective.277.356-361 Mucosal IgA may provide a barrier manifestations. Plasmodiumfalciparum causes the most 324 CHAPTER 10 rapidly progressive disease, including anemia, renal fail• The level of parasitemia is markedly enhanced by admin• ure, cerebral disease, pulmonary edema, liver failure, istration of corticosteroids in animal models. and death. Plasmodium viveu causes anemia and splenic Most patients will present with fever, chills, diar• rupture in severe cases. Plasmodium malariae may per• rhea, vomiting, anemia, myalgias, and fatigue.379-383 sist as an asymptomatic infection for many years and The clinical manifestations will depend on the species of may cause nephrotic syndrome in children. Plasmodium Babesia causing infection. Babesia microti causes mild ovale causes the acute infectious syndrome seen in all disease that appears to remit spontaneously.383 Patients forms of malaria. The acute presentations will be of rig• will have mild elevations in liver function tests and para• ors with high fever and sweats. Headache and nausea sitemia of less than 10%. Symptoms and parasitemia and occasionally seizures may be seen in all forms, but may exist for up to 4 months and are increased after are particularly important symptoms with P. Jalciparum. splenectomy. Babesia divergens has been seen in splen• As the life cycle of the organism become synchronized, ectomized hosts, with severe disease culminating in re• cycles of chills, fever, and sweats become characteristic nal failure, hypotension, and severe anemia. These in• for the species of malaria. Most patients will have non• fections have all been fatal. Diagnosis is by blood smear. specific complaints, including myalgias, cough, and di• Antibody-based tests are also available. 384 arrhea, and may have anemia, jaundice, or abdominal Treatment has been controversial, but therapy with tenderness. Relapse in malaria (P. onlle and P. vivax) clindamycin and quinine has been effective in some pa• may present years after initial infection. It is likely that tients.385.386 The high-grade parasitemia seen in splenec• infection is more severe in patients with functional or tomized patients or in those receiving corticosteroids has anatomic asplenia, during pregnancy, and possibly dur• responded to exchange blood transfusion in a few pa• ing immune suppression. 378 tients. It appears that pentamidine isethionate also re• Therapy is based on the type of malaria seen on the duces parasitemia. Quinine can be given in a dose of 650 peripheral blood smear and on the pattern of antibiotic mg orally 3 times a day with clindamycin at 600 mg resistance in the area in which it was acquired. If malaria orally 3 times or intravenously 3 or 4 times a day. is likely, the blood smears should be repeated after a negative examination, as the level of parasitemia may 11.4. American Trypanosomiasis fluctuate. Significant infection in immunocompromised (Chagas' Disease) individuals has been associated with transfusions of in• fected blood with P. malariae into immunocompromised Trypanosoma cruzi is a protozoan that infects man individuals. Transfusional disease will cause significant during a blood meal by the reduvid bug. These organ• infection in immunocompromised individuals. 378 isms develop intracellularly, releasing aflagellates that enter new cells and repeat the cycle. Trypanosoma cruzi 11.3. Babesiosis have a particular predilection for muscle (including car• diac) and neuroglial cells, and produce local inflamma• The babesiae are protozoan parasites of animals tion with lymphocytes, macrophages, and plasma cells. transmitted by the Ixodid tick to humans as an incidental In addition to reduvid infection, infection has occurred host. There are over 70 species of Babesia, several of as a result of organ transplantation and via blood transfu• which cause human disease, including B. microti and B. sion. Up to 20 million people are infected worldwide, divergens. Most of the cases of human babesiosis have including up to 40-50% of the population of endemic been described from the northeastern United States. A areas of Central and South America. Cases related to few cases of B. divergens have been reported from Eu• blood transfusion have been reported in the United States rope. Occasionally, babesiosis has been seen as a com• and Canada, as well as in endemic areas. plication of blood transfusion or in organ transplantation. The patient will present with fever, lymphadenopa• On the basis of serologic studies, it is likely that babesial thy, hepatosplenomegaly, and headache. A small, pain• infections occur worldwide but are asymptomatic or ful indurated area (chagoma) or unilateral orbital edema mildly symptomatic. with conjunctivitis (Romana's sign) will be present in The organism reproduces within erythrocytes, caus• many patients. The patient may develop symptoms of ing hemolysis and hemoglobinuria. Hypotension may re• myocarditis or meningoencephalitis. Sequelae of the sult from the release of a kallikrein activator by the or• acute infection may be seen many years after symptom• ganism. Splenectomy or abnormal splenic function and atic or asymptomatic initial infection. The major compli• T-lymphocyte dysfunction have been associated with es• cations of Chagas' disease are cardiac arrhythmias or pecially severe disease. Recurrent and apparently relaps• conduction defects with congestive heart failure. GI in• ing infection has been reported in a single AIDS patient. volvement may appear as megacolon or megaesophagus. PNEUMOCYSTIS CARINII AND PARASITIC INFECTIONS 325

Latent infection may be reactivated by immune suppres• 11.6. Cyclospora sion, including individuals who are the recipients of in• fected organ grafts. 1 A group of blue-green algaelike organisms (cyano• Treatment is with nifurtimox or benznidazole, but bacteria) has been implicated as the causative agent of a may fail to eradicate the parasite completely. severe diarrheal illness in travelers and in patients with AIDS.387-391 Electron microscopic studies have sug• gested that these "cyanobacteriumlike" bodies represent 11.5. African Trypanosomiasis a new protozoan pathogen of the coccidian genus Cyclo• African trypanosomiasis is caused by Trypanosoma spora. Like Cryptosporidium, this organism causes self• brucei, which causes African sleeping sickness. Infec• limited relapsing diarrheal illness in the normal host (up tion is initiated by the bite of the tsetse fly of Africa. to 3 months) and, possibly, persistent diarrhea in the few After being injected into the human host, the parasites cases described in patients with AIDS. Infection is most multiply locally, producing a chancre at the site of repli• often described in travelers after contact with contami• cation. Once in the bloodstream or within tissues, the nated water supplies in tropical regions. parasite evades immune detection through a process The organism is 8-10 fLm in diameter with a cluster called antigenic variation. A hemolyphatic phase of the (morula) of refractile, membrane-bound globule within a disease occurs, with bloodstream invasion weeks or limiting membrane. The organism is a thick-walled months after the initial chancre. This phase is charac• sphere with a fibrillar coat and granular cytoplasm. terized by fever, lymphadenopathy, fleeting rashes, There is no nucleus but a series of internal lamellar-type edema of face or legs, ascites, or pleural and pericardial structures similar to chloroplasts. Organisms stain with effusion. Jaundice and myocarditis may progress to rap• modified acid-fast and phenosafranin stains. Sheather's idly fatal complications. Trypanosomal invasion of the sugar flotation has been used to concentrate stool speci• basal ganglia produces meningeal inflammation extend• mens. Organisms can be excysted or sporulated in vivo ing into the brain cortex with perivascular cuffing. Per• in potassium dichromate. Cyclospora have been detected sistent headache and altered mental function will devel• following exposure to contaminated water and in trav• op, with a decreased level of consciousness commonly elers in tropical regions (up to 11 % of nonnative individ• termed "sleeping sickness." uals with diarrhea). Person-to-person spread was sug• This disease affects over 20,000 people a year. In gested by an outbreak occurring among medical contrast to most of the pathogens of importance to the housestaff in Chicago. Infection is most prominent in immunocompromised individual, African trypanosomia• small bowel, often in combination with other parasitic sis causes immune suppression sufficient to allow the infections. Malabsorption (as measured by D-xylose test• development of opportunistic infection, especially pneu• ing) is often present. No effective therapy has yet been monia. Because the treatment for infection is often toxic described for Cyclospora infection, based on controlled (suramin or melarsoprol), malnourished patients in en• clinical trials. demic areas need to have their nutrition and general clini• cal status optimized before they will tolerate treatment. Patients will often relapse after therapy. Many of the manifestations of the disease appear to be immune• References mediated. Generalized B-cell activation results in an in• crease in serum immunoglobulins (including autoan• 1. Joiner K, Sher A, Gaither T, et al: Evasion of alternative comple• ment pathway of Trl'pallosoma cruzi results from inefficient bind• tibodies) and immune complexes. Patients with African ing of factor B. Pmc Nat! Acad Sci USA 83:6593-6597, 1986. trypanosomiasis may also have diminished reactivity to 2. 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