The management of infections in the hematologically compromised patient presents an ongoing challenge. Diagnoses of hematologie disorders are frequently made at the time the patient presents with unusual and serious manifestations of common benign infections. Morbidity and mortality statistics in a variety of seemingly unrelated conditions - such as sickle cell anemia, spherocytosis, and leukemia - show that one of the most difficult aspects of long-term management of the hematologically compromised patient is the prevention and treatment of intercurrent infection.1"4
A basic understanding of the normal defenses against infection and a grasp of the effect of specific deficiencies on the host's ability to handle various infections are therefore essential.
Leukocytes of the peripheral blood play a major role in the host's fight against infection.
Phagocytes - including circulating neutrophils, eosinophils, basophils, monocytes, and the fixed-tissue histiocytes of the reticuloendothelial system - protect the host against pyrogenic bacterial and fungal infections.
Circulating lymphocytes are part of the lymphoid system, which includes the thymus and peripheral and gastrointestinal lymph nodes, and are necessary for the defense against viral and bacterial infections. The B-lymphocytes are essential for the production of antibody upon exposure to bacterial, viral, or fungal antigens and ensure that a given host will not repeatedly be prey to the same invader. T-lymphocytes respond to antigenic stimulation by "transformation" and elaborate substances that act in concert with the macrophages to protect the host against obligate intracellular infectious agents, such as virus, acid-fast bacilli, etc. Thus, unusual susceptibility to infection in the hematologically compromised host is due to two types of disorders, disorders of nonspecific defenses and disorders of specific defenses.
DISORDERS OF NONSPECIRC DEFENSES
The phagocytes are probably derived from a common stem cell. A period of five to six days seems necessary for the myeloblast to proliferate and mature to the myelocyte stage, with an additional two days necessary for the maturation to the band or polymorph stage. Phagocytic capacity begins at the myelocyte stage but is not maximal until the band stage.5'6 Under normal circumstances, for every 100 granulocytes in the bone-marrow pool, one neutrophil circulates (circulating pool) and an additional neutrophil is marginated along the endothelium of the vascular tree (marginal pool). The half-life of circulating neutrophils has been estimated at six to seven hours, and the rate of their disappearance from the circulating pool seems to be dependent on the need for their appearance in extravascular areas - i.e., a focus of bacterial infection will result in increased demand and therefore in their increased disappearance from the circulating pool.
Leukocytosis may thus be due to either mobilization of the m argina ted leukocyte pool or to release of the bone-marrow leukocyte reserve, and Ieukopenia is due to an imbalance between leukocyte utilization in the extravascular compartment and leukocyte release from the marrow granulocyte pool. Replacement of granulocytes by transfusion of exogenous cells results in a very short-lived rise in circulating neutrophils.
The monocyte is also produced in the bone marrow; but, unlike the neutrophil, it is not stored. Circulating monocyte levels increase in chronic infection. In addition to its phagocytic role, the monocyte plays a part in the lymphocyte transformation necessary for cellular immunity.7,8
Inflammation and accumulation of exudate constitute a complex process that begins with the migration of phagocytes to the site of tissue injury and results in the death of the invading bacterium. The following steps have been identified:
Migration of phagocytes, mediated by such chemotactic factors as "filtrates" from bacterial cultures and "complement complexes."
Opsonization, or the attachment of the bacterium to the phagocyte wall, facilitated by the presence of specific antibody and complement or by the "heat labile'* opsonin system.
Ingestion, or the invagination of the cell wall with its attached bacterium, and the formation of a phagosome.
Killing of the bacterium within the phagosome through the action of lysosomal and peroxidative enzymes,9"11
Should the invading organism find its way into the bloodstream, the reticuloendothelial system, especially the spleen, acts as a filter and a secondary locus is established where a similar defense can be attempted. Finally, as time elapses, specific antibody production proceeds and the opsonization process becomes simplified and more efficient. Thus, it becomes clear that diseases that (1) diminish production of phagocytes, (2) contribute to their increased destruction, or (3) interfere with their specific function result in an inability to contain pyogenic bacterial or fungal infection. Attempts at replacement therapy are greatly limited by the survival time of functioning phagocytes and therefore require facilitation of phagocytic function with bactericidal antibiotics or specific antibody in addition to neutrophil transfusions.
DISEASES OF THE RETICULOENDOTHELIAL SYSTEM
In addition to its nonspecific function as a filter, the spleen apparently possesses lymphocytes capable of producing specific opsonizing antibody within a short time after first exposure to an antigen administered intravenously.
This offers a possible explanation for the unusual susceptibility of the postsplenectomy patient or of the autosplenectomized sickle cell anemia patient to overwhelming sepsis due to pyogenic microorganisms, such as pneumococci or Hemophilus influenzae. 12~15
Daily penicillin prophylaxis has been advocated for the splenectomized patient.
Diseases of the B-lymphocyte system result in the host's inability to invoke defense mechanisms against bacteria other than the nonspecific primary inflammatory response. The specific antibody response will be lacking. The host will be repeatedly exposed to injury from the same organism. Opsonization and final kill will not be facilitated with time unless the specific antibodies to commonly occurring organisms can be provided from external sources - i.e., immune-globulin injections.16
T-cell deficiency in patients results in an inability to withstand viral or opportunistic infections and in persistent infection, progressing more or less rapidly but inexorably to a fatal outcome.17,18 In addition, because there are no defenses against foreign cells, transfusion of lymphocytes in these patients results in a graft-versus-host reaction.
MANAGEMENT OF INFECTIONS
It is imperative that a complete assessment of the hematologically compromised patient be obtained at the onset of a suspected episode of infection. Treatment must be aimed at (!) making up for the host's deficient defenses whenever possible, (2) selecting the most effective antimicrobial agents available against a given invader, and (3) maximizing the host's healing abilities by maintenance of a normal coagulation system and of an optimal nutritional state.
In certain extreme situations - e.g., in the patient with thymic aplasia or with leukemia in relapse following several years of chemotherapy - the only practical approach to infection is an attempt at complete prevention, because this type of host succumbs readily to invasion by any organism, including those present in the normal intestinal flora. Such an attempt entails (1) isolation in a laminar-flow room, (2) gut sterilization, and (3) sterilization of all foods and supplies to be utilized by such patients. This regimen is followed until the patient's own defenses can be reconstituted by response to chemotherapy or by transplantation with cells from a compatible donor.
In all other situations, prevention of infection or early intervention is essential. Thus, proper management begins by parent education. Parents must be taught to report signs of infection in their child immediately, since any infection is likely to have much more serious consequences in the hematologically compromised host. Of course, any exposure to children with varicella or shingles, or any of the common childhood diseases for which the child has not been vaccinated, should also be reported promptly.
Hospitalization should be avoided if possible. Hospital stays, when necessary, should be kept as short as possible, to minimize the chances of colonization with nosocomial organisms. Hospital-acquired organisms are frequently resistant to all the commonly available antibiotics. Extreme care must be taken, therefore, and all procedures performed under strict aseptic techniques. Intravenous catheters must be avoided if at all possible; if placed, they must be changed at frequent intervals and cultured daily.
The pediatrician himself must maintain an awareness of the diseases prevalent in the community and of his patient's history, recent ability to handle various types of infections, and recent antibiotic therapy.
Attention to these historical factors frequently provides definite clues to a specific infectious agent and facilitates immediate selection of appropriate preventive steps or an optimal therapeutic regimen.
In the absence of specific clues, a broad attack against all possible invaders should be mounted following culture of as many sites of infection as it is safely feasible to do. The absence of a polymorphonuclear response to invading organisms is obviously the rule in an agranulocytic patient; hence the usual laboratory parameters, such as white cell count in various body fluids, are not reliable. The only ultimate proof of absence of bacterial or fungal infection can be the obtaining of repeatedly negative cultures of blood, urine, transudates, cerebrospinal fluid, and bone marrow.
Since the most common infections are bacterial and since the agranulocytic host is equally susceptible to pyogenic gram-positive organisms and to saprophytic gram-positive and -negative organisms, antibiotics bactericidal to both types must be started in high intravenous dosage before culture results are available. Recommended regimens usually include cephalothin (Keflin®), 50 mg./kg./day, administered intravenously in six-hourly doses, each infused over one hour; gentamicin (Garamycin®), 3 mg./kg./day, given intravenously every eight hours infused over one hour; and carbenicillin (Geopen®), 50-200 mg./kg./day, given intravenously every four hours infused over one hour.19 Treatment with these drugs is continued until a specific agent has been isolated and its sensitivities have been ascertained or for 10 days if the initial response was satisfactory.
Because the inflammatory process is accompanied by damage to vascular endothelium and increased capillary permeability, platelets are essential for the prevention of bleeding at the site of inflammation. They must be supplied from exogenous sources if bone marrow is unable to produce them.
If the clinical response to antibiotics is inadequate and bacterial cultures taken on repeated occasions are negative, viral, fungal, acid-fast, or parasitic infections must be considered and appropriate therapy attempted.
Children most often contract tuberculosis from household contacts. The tuberculin test is usually negative in the immunosuppressed patient. Tuberculin testing of all other members of the household is helpfuHn determining the possibility of tuberculous infection in the patient with an incompetent cellular immune system. In the presence of tuberculin-positive members of the immediate family, isoniazid should be started until acid-fast culture results are available. The risk of untreated tuberculosis in the imm unoin competent patient is much greater than the risk of a two-month course of isoniazid. The infiltrates of miliary tuberculosis with adenopathy and splenomegaly can mimic tumor relapse, and tissue diagnosis is essential in this circumstance.
Fungal infections are a special risk to the patient with defects of both the nonspecific and specific defense mechanisms. The leukemic child whose bone-marrow granulocyte reserve has been chronically depleted by combination chemotherapy, whose immunologie system has been depressed by a combination of immunosuppressive drugs and high-dose steroid treatment, and whose bacterial flora has been significantly altered by recent administration of antibiotics is a candidate for disseminated fungal infections. Candida and Aspergillus are the most frequent causative agents.20,21 The diagnosis can be established by demonstrating fungi in cultures of body fluids, bone marrow, urinary tract; culture of suspicious skin; mucous membrane lesions; or the appearance on chest x-ray of the typical fungus ball lesions.
Systemic fungal infections require treatment with amphoteridn B.22 The initial dose is 0.1 mg./kg./day, administered intravenously in a solution of 5 per cent dextrose water over a period of four to six hours. If the dose is toicrated, it is gradually increased to a maximum dose of 1 mg./kgVday and continued for four to 12 weeks. Side effects include fever, chills, nausea, and vomiting. Toxicity includes damage of renal function with azoternia and potassium loss.
The common viral infections are much more serious in the hematologically compromised host, especially in the patient whose cellular immune system functions improperly - either on a congenital basis, as in the various inherited immune-deficiency syndromes, or on an acquired basis, as with the leukemic patient maintained on immunosuppressive chemotherapy for a number of years.23
In these children, even generally innocuous viruses - such as the vaccinia virus, the attenuated measles vaccine virus, or the Sabin oral polio vaccine virus - have resulted in fatal infections with severe hepatic and pulmonary involvement.23'25
Owing to the unavailability of nontoxic agents, prevention of viral infections is essential.
Live virus vaccines must be avoided.25 Specific hyperimmune globulin may be administered, when available, immediately following exposure to the infectious agent or at regular intervals during epidemics. Zoster immune serum globulin or massive doses of commercial gamma globulin (0.6 ml./lb.) have been reported to prevent varicella.26 Progressive varicella pneumonia has, in some instances, responded to treatment with cy tosine arabinoside in a dose of 1-3 mg./kg./day.27,28 In addition to the danger from common childhood diseases, disseminated infections with herpes simplex and cytomegalovirus have been reported; treatment with floxuridine by intravenous push (20 mg./kg./ day for five days) and prednisone (2 mg./kg./ day for five days) has shown some promise.29 Success was also reported recently in the treatment of herpes simplex encephalitis with adenine arabinoside therapy, at a dosage of 15 mg./kg./day over 12 hours, in concentrations not exceeding 0.7 mg./ml. of standard intravenous solutions.30
PNEUMOCYSTlS CARINII PNEUMONIA
In the hematologically compromised patient, Pneumocystis carinii pneumonia must be considered in the differential diagnosis of any diffuse i n filtrat i ve lung disorder. Diagnosis is suspected when the child has a pneumonic infiltrate, accompanied by fever and respiratory distress, that is unresponsive to multiple-antibiotic therapy. The development of capillary alveolar block characterized by rapid clinical deterioration frequently makes an attempt at specific diagnosis difficult.
On occasion, the organism may be identified from bronchial brushings obtained at endoscopy or from lung biopsy.31,32 Until recently, the only available form of treatment was pentamidine isethionate* 4 mg./kg. day, administered intramuscularly for 15 days).32'33 More recently, pyrimeth amine and sulfadiazine by the oral route have been advocated for the treatment of P. carinii infections.34
The topic of special problems of infectious diseases for the hematologist is not completely covered without at least brief mention of hemolytic diseases with hemolytic and aplastic crises precipitated by infection or by drugs utilized in the treatment of infections. GIucose-6-phosphate dehydrogenase deficiency is the prototype of these hemolytic anemias. In clinical practice, hemolytic episodes secondary to infections may be more frequent than episodes related to drug ingestion.35 The crisis is usually moderately severe, and because of the depressant effect of infection on marrow erythropoietic function, the reticulocyte count may show no significant rise. Elevated body temperature, hydrogen peroxide produced by phagocytic cells, and direct viral action have all been evoked as causative agents.36"38
In summary, the hematologically compromised host is at serious risk of morbidity and mortality from infections caused by a variety of pathogenic agents, some of which are pathogens only in the debilitated patient. He must, therefore, be protected from infection as much as possible and must be vigorously treated at the first sign of infection. Treatment has to be prolonged in order to make up for the lack of host defenses, whether it is the treatment of an abscess in chronic granulomatous disease or the treatment of pneumonia in a leukemic patient in remission.
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