Pneumonia in immunosuppressed patients

Blackwell Science, LtdOxford, UKRESRespirology1323-77992004 Blackwell Science Asia Pty LtdMarch 20049S1S25S29Original ArticlePneumonia in immunosuppressed patientss Kohno et al. Respirology (2004) 9, S25 S29 CHAPTER 6 Pneumonia in immunosuppressed patients The committee for The Japanese Respiratory Society guidelines in management of respiratory infections The Japanese Respiratory Society Pneumonia in immunosuppressed patients The committee for The Japanese Respiratory Society guidelines in management of respiratory infections. Respirology 2004; 9: S25 S29 WHAT IS IMMUNOSUPPRESSION? Immunosuppression occurs as a result of a lack of either humoral (B-cell) immunity or cellular (T-cell) immunity, or both. While immunosuppression plays a central role in susceptibility to infectious diseases in humans, neutropenia is another important contributing factor. In this chapter, immunosuppression in its broad sense will be discussed, including lack of neutrophil-mediated immunity as well as lack of humoral (B-cell) immunity and cellular (T-cell) immunity. Patients develop a variety of infectious diseases as a result of immunosuppression, and the lung is one of the most susceptible vital organs. TYPES OF IMMUNOSUPPRESSION AND FEATURES OF PNEUMONIA IN IMMUNODEFICIENT PATIENTS 1 Neutropenic patients often have fevers but seldom exhibit pneumonia-related symptoms. The chest X-rays of neutropenic patients rarely show evidence of infiltration, and such patients seldom produce purulent sputum. 1 The severity and duration of the neutropenia affects patients susceptibility to pneumonia and the prevalence of causative microorganisms. 2,3 (i) Severity of neutropenia Neutrophil count 1000/mL: Patients begin to show susceptibility to infection. Neutrophil count 500/mL: Patients show striking susceptibility to infection. Neutrophil count 100/mL: Patients have almost completely lost neutrophil-mediated defence functions. (ii) Duration of neutropenia No more than a few days: Susceptibility to infection low, seldom presents with clinical problems. Less than 3 weeks: Patients show increased risk of bacterial infection(s). More than 3 weeks: Patients show increased frequency of fungal infection as well bacterial infection. 2 The major high risk factors for neutropenia are shown below (i) Primary neutropenia: Genetically inherited neutropenia and periodic neutropenia are wellknown, but their incidence is low. (ii) Secondary neutropenia: associated with acute leukaemia and aplastic anaemia. (iii) Iatrogenic neutropenia: associated with the use of myelosuppressive anticancer chemotherapy, radiation therapy, and bone marrow transplantation, as well as with drug-induced granulocytopenia. 3 commonly associated with neutropenic patients and pneumonia Most causative agents of pneumonia in neutropenic patients are bacteria that proliferate extracellularly (primarily pyogenic bacteria) and fungi (Aspergillus in particular). Other bacteria are rarely associated with pneumonia in neutropenic patients. (i) Gram-positive bacteria: including Staphylococcus aureus and pneumoniae. Gram-negative bacteria: including Pseudomonas aeruginosa, Klebsiella and E. coli. (ii) : including Aspergillus and Mucor. Humoral immunosuppression The committee for The Japanese Respiratory Society guidelines in management of respiratory infections, 2-6-4 Kanda, Chiyoda-ku, Tokyo 101-0047, Japan. 1 Three types of humoral immunosuppression are known: lack of immunoglobulins as a whole, lack of a specific subclass of immunoglobulins, and defec-

S26 tive immune response to specific antigens. Most humoral immunosuppression occurs as a result of impaired IgG synthesis in vivo. 4 (i) Severity of the decreased IgG level 5 More than 500 mg/dl: Patients seldom develop infection(s). 200 500 mg/dl: Patients begin to show susceptibility to infection. Less than 200 mg/dl: Patients show increased susceptibility to infection paralleling the decrease in serum immunoglobulin level. 2 The major high-risk factors for humoral immunosuppression are shown below. (i) Primary humoral immunosuppression: Severe complex humoral immunodeficiency syndrome and X-chromosome linked agammaglobulinaemia are well-known forms of primary humoral immunodeficiency, but their incidence is low. (ii) Secondary humoral immunosuppression: multiple myeloma, chronic lymphocytic leukaemia, some types of malignant lymphoma, some cases of HIV infection, severe nephrotic syndrome, burns, and protein-losing enteropathy. (iii) Iatrogenic neutropenia: humoral immunosuppression associated with the use of myelosuppressive anticancer chemotherapy, radiation therapy, and bone marrow transplantation. 3 commonly associated with humoral immunosuppression and pneumonia: Since opsonization via attachment of antibodies on the organisms, production of neutrophil chemotactic factor and complement activation are impaired, the host s defences against capsule-containing bacteria which correlate with opsonizing antibodies are primarily impaired. Other bacteria are rarely associated with hospital-associated pneumonia in patients with humoral immunosuppression. : includes pneumoniae, H. influenzae and Klebsiella. Cellular immunosuppression 1 The CD4-positive lymphocyte counts of patients with cellular immunosuppression affect their susceptibility to pneumonia and the prevalence of causative microorganisms. 6 Table 1 shows the corre- S Kohno et al. lation between CD4-positive lymphocyte counts and prevalent disorders among patients with HIV infection. (i) Severity of lymphopenia (CD4-positive lymphocyte count) CD4-positive lymphocyte count 500/mL: Patients do not show any particular susceptibility to infection. Common bacterial pneumonia is seen. CD4-positive lymphocyte count < 500/mL: Patients develop tuberculosis and cryptococcosis more frequently than healthy individuals. CD4-positive lymphocyte count 200/mL: Patients are susceptible to opportunistic pneumonia caused by a variety of pathogenic microorganisms, including viruses and parasites. CD4-positive lymphocyte count 50/mL: Patients have almost completely lost CD4-positive lymphocyte-mediated defence function. 2 The major high risk factors for cellular immunosuppression are shown below. (i) Primary cellular immunodeficiency: DiGeorge syndrome and other disorders are known, but the incidence of these diseases is low. (ii) Secondary cellular immunosuppression: including HIV infection, Hodgkin s disease, chronic lymphocytic leukaemia and some types of malignant lymphoma, etc. (iii) Iatrogenic cellular immunosuppression: cellular immunosuppression associated with the use of adrenocortical steroid preparations, immunosuppressive agents, myelosuppressive anticancer chemotherapy, radiation therapy, bone marrow transplantation and organ transplantation. 3 Common bacteria associated with cellular immunosuppression and pneumonia: Reduced CD4-positive lymphocyte counts result in defects of cytokine production. As a result, macrophage activation is impaired, which leads to loss of bactericidal activity. Patients with cellular immunosuppression become susceptible to pneumonia caused by these microorganisms, and once they develop pneumonia it becomes severe. CD4-positive lymphocytes also induce the differentiation of B- lymphocytes and natural killer cells, and this activity is also impaired. As a result, humoral immunity and the elimination of virus-infected cells (i.e. the immunological defence system) are also impaired. Because Table 1 CD4-positive lymphocyte count and prevalent pulmonary lesions in HIV-positive patients CD4-positive lymphocyte count CD4-positive lymphocytes 500/mL CD4-positive lymphocytes 200/mL CD4-positive lymphocytes 50/mL Prevalent pulmonary lesions l pneumonia ( pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa) Tuberculosis (typical pathological conditions if CD4- positive lymphocytes 200/mL, atypical pathological conditions if CD4-positive lymphocytes < 200/mL Kaposi s sarcoma (preceded by dermatological lesions) Pneumocystis carinii pneumonia Cryptococcosis (pulmonary lesion is part of systemic infection) Toxoplasmosis (pulmonary lesion is part of systemic infection) Malignant lymphoma (pulmonary lesion is part of systemic lesions) pneumonia (pulmonary lesion is part of systemic infection) Non-tuberculous atypical mycobacteriosis (rarely restricted to the pulmonary lesion)

Pneumonia in immunosuppressed patients of this, a variety of causative microorganisms have been isolated from pneumonia patients with cellular immunosuppression. (i) : pneumoniae, Pseudomonas aeruginosa, Legionella, Nocardia and Mycobacterium. (ii) Viruses: and herpes simplex virus. (iii) : Pneumocystis carinii, Aspergillus, Cryptococcus, mucor and candida. (iv) Protozoa and parasites: including Toxoplasma and Strongyloides stercoralis. DIAGNOSIS OF PNEUMONIA IN PATIENTS WITH IMMUNOSUPPRESSION (Fig. 1) Primary examination S27 1 If a patient is suspected of having pneumonia based on their presenting history, symptoms (cough, sputum, fever, dyspnoea, chest pain, etc.), leukocytosis, elevation of CRP, or infiltration on chest X-rays (as shown in Table 2), the primary examinations listed below should be performed, and immunosuppression should be assessed in accordance with the following criteria: (i) Neutrophil count 500/mL. (ii) Humoral immunosuppression IgG 500 mg/dl. (iii) Cellular immunosuppression CD4-positive lymphocyte count 200/mL. 2 Primary examination Haematological examinations (with a haemocytometer): WBC counts (leukocyte counts), leukocyte fractions, CD4-positive lymphocyte counts, CD8- positive lymphocyte counts, CD4/CD8 ratio, and CRP (C-reactive protein). (i) Erythrocyte sedimentation rate (ESR): ESR at one hour. (ii) Immunoglobulins: IgG, IgA, and IgE. (iii) Blood gas analysis (iv) Chest X-ray: posteroanterior and lateral (v) Microbiological examinations Primary examinations Hematological examinations WBC count and leukocyte fractions CD4, CD8, and CD4/ CD8 ratio CRP ESR IgG Blood gases Chest X-ray Microbiological examinations General bacterial, acid-fast bacterial, fungal, and blood culture Neutrophil count 500/µl Staphylococcus aureus, pneumoniae, Pseudomonas aeruginosa, Klebsiella, and E. coli Aspergillus and Mucor Itraconazole + 3rd generation cephems or 4th generation cephems or carbapenems Pneumonia IgG 500 mg/dl Humoral immunodeficiency Haemophilus influenzae, pneumoniae, and Klebsiella Immunoglobulin + 3rd generation cephems or 4th generation cephems or carbapenems CD4-positive lymphocyte counts 200/µl Cellular immunosuppression pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Nocardia, and mycobacterium Virus Pneumocystis carinii, Cryptococcus, and Aspergillus Secondary examinations Imaging CT Antigen tests : Legionella : b-glucan, Aspergillus, Cryptococcus, Candida Virus: PCR:, Mycobacterium, and Pneumocystis carinii Skin reactions Tuberculin-reaction Invasive examinations Bronchoscopy: Bronchoalveolar lavage, brushing, curettage, and biopsy Bilateral infiltration and/or PaO 2 70 Torr ST mixture + Fluoroquinolones + Itraconazole + 3rd generation cephems or 4th generation cephems or carbapenems Others Itraconazole + 3rd generation cephems or 4th generation cephems or carbapenems Figure 1 Flowchart for diagnosis, treatment and laboratory tests for hospital-acquired pneumonia among patients with immunosuppression.

S28 S Kohno et al. Table 2 Causative microorganisms responsible for infiltration seen on chest X-ray Characteristics of infiltration Classification Causative microorganisms Infiltration Nodular infiltration Cavity formation Diffuse interstitial infiltration Fungus Virus Fungus Common bacteria, Legionella (multiple infiltration), Mycobacterium tuberculosis (miliary infiltration, characterized by numerous tiny densities on radiographs) Cryptococcus Nocardia Aspergillus, Cryptococcus, and Mucor Staphylococcus aureus, Klebsiella, Pseudomonas aeruginosa Nocardia, and Mycobacterium tuberculosis Aspergillus Pneumocystis carinii Sputum culture general bacterial smear. Sputum culture acid-fast bacterial smear. Sputum culture fungal smear. Blood culture. 3 Secondary examinations If a patient is diagnosed with immunosuppression (neutropenia, decreased IgG level and/or decreased CD4-positive lymphocyte count), empiric therapy should be instituted based upon the result of the primary examination. The following secondary assessments should be performed in parallel to isolate and identify the causative microorganisms. Secondary examinations 1 Diagnostic imaging: CT (computed tomography). 2 Antigen tests (i) : Urinary Legionella antigen level: sensitivity and specificity 90%. (ii) : b-d-glucan: If positive for b-d-glucan ( 20 pg/ ml), fungal infection or Pneumocystis carinii infection should be suspected. However, false-positive responses are also noted for Cryptococcus. Aspergillus antigen: high specificity but low sensitivity; (iii) Cryptococcus antigen: sensitivity = 90%, specificity = 90%. (iv) Candida antigen: Sensitivity and specificity are both poor. (v) Viruses: cytomegalovirus antigen (viraemia or antigenaemia assay). (vi) PCR: cytomegalovirus; Mycobacterium: Mycobacterium tuberculosis and atypical mycobacterium; Pneumocystis carinii. 3 Skin reactions Tuberculin reaction: False-negative responses are often noted in patients with cellular immunosuppression, and the tuberculin test is not reliable. 4 Invasive examinations Bronchoscopy: Bronchoalveolar lavage (BAL), brushing, curettage, and lung biopsy (TBLB). Problems associated with assessing immunosuppressed patients with pneumonia 1 When immunosuppressed patients develop pneumonia, there may be more than one microorganism involved. Since more than one microorganism can be simultaneously involved, always keep in mind that multiple microorganisms may cause pneumonia. 2 Colonisation by pathogenic microorganism is frequently noted in patients with immunosuppression. Consequently, in many patients with immunosuppression, the bacteria isolated are not necessarily the causative microorganism. (i) Microorganisms where there is little doubt that they are the causative agents. : Legionella, Mycobacterium tuberculosis; : Pneumocystis carinii, Cryptococcus and Mucor. (ii) There is a possibility that the microorganisms isolated are not the causative agents. : MRSA, Pseudomonas aeruginosa andnon-tuberculosis Mycobacterium (atypical mycobacterium). : Candida. Viruses: cytomegalovirus (particularly in AIDS). EMPIRIC THERAPY FOR PNEUMONIA IN IMMUNOSUPPRESSED PATIENTS (I.E. TREATMENT BASED ON THE RESULTS OF PRIMARY EXAMINATION) 1 Generally, common bacteria and fungi are often the causative microorganisms in hospital-acquired pneumonia in a setting of neutropenia, and since the pneumonia may very rapidly worsen, empiric therapy with the antibacterial agents listed below must be instituted immediately.; (i) If the neutrophil count is between 500/mL and 1000/mL, one of the following should be used:

Pneumonia in immunosuppressed patients (ii) If the neutrophil count is below 500/mL, one of Itraconazole + one of the following; Third generation cephem antibiotics + aminoglycosides; G-CSF facilitates improvement of pneumoniarelated symptoms by shortening the duration of neutropenia. 7 Humoral immunosuppression 1 In most patients with humoral immunosuppression, bacteria are the cause of the pneumonia. In addition, the prevalence of H. influenzae and pneumoniae is quite high. Approximately 10 20% of H. influenzae are b-lactamase-producing strains, and non-b-lactamase-producing ampicillinresistant H. influenzae (BLNAR) strains constitute approximately 30% of the bacterial strains isolated from clinical specimens. 8 It has been reported that approximately 50% of pneumoniae strains have poor sensitivity to penicillin (PISP) or are resistant to penicillin (PRSP). 9 In view of the current situation, the following empiric therapy should be selected. (i) If the IgG level is no more than 500 mg/dl, one of Immunoglobulin + one of the following; Cellular immunosuppression 1 A wide variety of pathogenic microorganisms may cause pneumonia in patients with cellular immunosuppression, making it impossible to select empiric therapy that is effective against all of them. For this reason, empiric therapy should be instituted taking common bacteria as well as Pneumocystis carinii and Legionella (which cause rapidly progressive pneumonia) into consideration; (i) If the CD4-positive lymphocyte count is between 200/mL and 500/mL, one of the following antibiotics should be used: S29 (ii) If the CD4-positive lymphocyte count is less than 200/mL or if bilateral infiltration is seen on the chest X-ray and/or PaO 2 is 70 Torr, one of the following combinations should be used: ST mixture 12 tablets/day + Fluoroquinolone + Itraconazole + one of the following; (iii) If the above criteria are not applicable, one of Itraconazole + one of the following: Carbapenems. REFERENCES 1 Sickles EA, Greene WH, Wiernik PH. Clinical presentation of infection in granulocytopenic patients. Arch. Intern. Med. 1975; 135: 715 9. 2 Bodey GP, Buckley M, Sathe YS et al. Quantitative relationship between circulating leukocytes and infection in patients with acute leukemia. Ann. Intern. Med. 1966; 64: 328 40. 3 Gerson SL, Talbot GH, Hurwitz S et al. Prolonged granulocyto-penia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann. Intern. Med. 1984; 100: 345 51. 4 Shelhamer JH, Toews GB, Masur H et al. Respiratory disease in the immunosuppressed patient. Ann. Intern. Med. 1992; 117: 415 31. 5 Schiff RI. Treatment of primary immunodeficiency diseases with gammaglobulin. In: Lee M, Strand V (eds). Intravenous Immunoglobulins in Clinical Practice. Marcel Dekker, New York, 1997; 175 92. 6 Masur H, Ognibene FP, Yarchoan R et al. CD4 counts as predictors of opportunistic pneumonias in human immunodeficiency virus (HIV) infection. Ann. Intern. Med. 1989; 111: 223 31. 7 Mather DW, Lieschke GJ, Green M et al. Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial. Ann. Intern. Med. 1994; 121: 492 501. 8 Ubukata K. Isolates from specimens sent by members of Study Groups and the drug sensitivity of the isolates. Jpn J. Antibiot 1998; 52: 48 56. 9 Matsumoto K, Shiraishi T, Rikimaru T et al. Resistance against oral antibiotics to pneumoniae isolated from adult respiratory tract infections. Jpn J. Antibiot 1999; 73: 1187 93.