Respiratory infections in immunosuppressed patients

Chapter 9

Respiratory infections in immunosuppressed patients

S.R. Konduri

A.O. Soubani    Wayne State University School of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Detroit, Michigan, United States


Immunosuppression is a common phenomenon in clinical practice. It could be related to underlying malignancies, therapeutic interventions, or other congenital and acquired conditions affecting the immune system. There have been significant advances made in the treatment of malignancies. Although the newer chemotherapeutics have fewer adverse effects, infection remains a major cause of morbidity in these patients. Respiratory infections represent a significant number of these infections. These may range from limited viral infections to life-threatening bacterial and fungal infections. This chapter will provide an update on the spectrum of respiratory infections in non-HIV immunosuppressed patients, focusing on those with hematological malignancies, describing the incidence, risk factors, diagnosis, management, and outcome of these infections.


immunosuppressed patient

hematological malignancy

respiratory infections


1. Introduction

Alterations of the immune system are common. They could be due to hematological malignancies such as acute leukemia, tissue and organ transplantation, primarily hematopoietic stem cell transplantation (HSCT); and chemotherapeutic and immunosuppressive medications used for the treatment of a variety of malignant and nonmalignant conditions. Also, disruption in the anatomical barriers and invasive procedures are other causes of altered immune states.

Pulmonary complications, both infectious and noninfectious, are important cause of morbidity and mortality in immunosuppressed (Fig. 9.1). The incidence of these complications reaches 60% of patients.1,2 The mortality of pulmonary complications is 40% and approaches 90% in patients who require mechanical ventilation.3 The etiology of pulmonary disease in immunosuppressed patients may be predicted based on variables such as the type of immunodeficiency, the presence of neutropenia, the prophylactic agents being used, and the temporal relation to the administration of chemotherapy.


Figure 9.1 The Spectrum of the Main Respiratory Complications in Immunosuppressed Patients

2. Pathophysiology predisposing patients to infections

The risk of infection in immunosuppressed patients primarily stems from defects in the number or function of neutrophils, T cells, and B cells. Abnormalities in each of these cell lines increases the risk of specific infections (Fig. 9.2). However the functions of these defense mechanisms are interdependent, so an abnormality in one cell line may compromise the function of other defense mechanisms. Neutropenia is the most frequent immunodeficiency in patients with hematological malignancies. It is seen in patients with acute leukemia and secondary to myelosuppression following chemotherapy. It has been previously shown that the neutrophil function is suppressed in some cancers, which consequently increased risk of infection after chemotherapy.4 In addition to decreasing the production of neutrophils, de novo cancer,57 chemotherapy and radiation interfere with the chemotactic, phagocytic activity, and the intracellular killing of microorganisms by these cells. Furthermore, corticosteroids, which are part of treatment of many conditions, are well known to cause peripheral neutrophilia by reducing their adherence to endothelial cells and chemotactic properties. Neutrophils are protective against bacterial and fungal infections. The risk of infection in neutropenia increases below an absolute neutrophil count (ANC) of 500 cells/m3. The risk increases significantly with ANC < 100 cells/m3. The duration of neutropenia and rate of decline of ANC count also individually pose risk for acquiring infection. In fact, almost all patients with ANC <100/m3 for more than 3 weeks become febrile. Aspergillosis is one such infection that highlights these risk factors in patients with neutropenia. In a study on patients with Aspergillus infections, the authors have noted that the risk of Aspergillus infection was increased by 1% with each day of neutropenia for the first 3 weeks, thereafter the risk increases by 4%.8


Figure 9.2 The Mechanisms, Causes, and Infections Associated With Immunosuppression

B cells are responsible for the humoral branch of the immune system. They produce immunoglobulins (IgM, IgG, IgE, IgA, and IgD) after appropriate stimulus by the antigen-presenting cells. Abnormalities in their number and function, predispose to infection with encapsulated bacteria such as Streptococcus pneumoniae, Hemophilus influenzae, and Staphylococcus aureus. Lymphoproliferative malignancies such as chronic lymphocytic leukemia, multiple myeloma, treatment with monoclonal antibodies such as Rituximab, and intensive chemotherapy regimens are some of the other scenarios where B cell abnormalities are seen.

T-cells are responsible for cellular-mediated immunity. They play a vital role by regulating monocyte-macrophage antigen handling, production of cytokines and intracellular pathogen elimination. Abnormalities in T-cell function predispose to infections from organisms such as Aspergillus and Pneumocystis jirovecii, viruses, Nocardia and Mycobacteria. Corticosteroids, immunosuppressants such as Tacrolimus, Sirolimus, Azathioprine, chemotherapeutic agents like cyclophosphamide, fludarabine, cladribine, anti-CD52 monoclonal antibodies (Alemtuzumab) impair T-cell function.

Violation of anatomical barriers, resulting from invasion by cancer or by its treatment, also increases risk for infection. For example, mucositis secondary to chemotherapy may predispose to aspiration or translocation of microorganisms from the gastrointestinal tract, vascular catheters inserted for chemotherapy, parenteral nutrition, and transfusion of blood products may be sources of bacterial and fungal infections.

3. Bacterial pneumonia

Bacterial pneumonia caused by Gram-positive and Gram-negative organisms is a significant problem in patients with malignancies and is a leading cause of infectious death in these patients. It constitutes about 34% of the infectious episodes in patients with acute leukemia.9 They account for 15% of all respiratory infections.10 Up to 60% of patients with neutropenia can develop lung infiltrates during the course of their disease.11 These bacteria may lead to community and hospital acquired pneumonia.

Factors that generally increase the risk of bacterial pneumonia in immunosuppressed patients include the nature of the immunodeficiency, chemotherapeutic regimen, degree, and duration of neutropenia.2,12 Other factors that may predispose to bacterial pneumonia include older age, lower performance status,13 mucositis that increases the risk of aspiration14 and indwelling catheters that increase the risk of bacteremia and septic emboli to the lungs.15

Certain characteristics of immunosuppression may predispose the patient to particular organisms. For example, encapsulated bacteria like S. pneumoniae, H. influenzae are seen more frequently in patients with multiple myeloma, chronic lymphocytic leukemia. Legionella pneumophila is more frequently seen in patients with lymphoma.

The presentation of bacterial pneumonia in these patients may be subtle, and not infrequently, patients present with neutropenic fever without localizing symptoms and signs due to blunted inflammatory response.16 Radiological signs may also be subtle and scarce. The chest radiograph usually shows focal consolidation. However, they may be normal. The infiltrates may progress quickly to multifocal or diffuse changes that are compatible with acute respiratory distress syndrome. High resolution computerized tomography of the chest (HRCT) is recommended in febrile neutropenic patients, as it may show pulmonary infiltrates in up to 50% of patients with negative chest radiograph.17 Many patients need invasive procedures like bronchoscopy for obtaining adequate samples for culture and serological testing. This is mainly due to a lower yield on sputum as a result of oropharyngeal contamination, use of prophylactic antibiotics, and so on.

The organisms frequently isolated are Gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella spp, Escherichia coli, Moraxella catarrhalis, H. influenzae, Stenotrophomonas maltophilia18 and Gram-positive organisms (patients without a recent antibiotic exposure) like S. pneumoniae and S. aureus.19 A 10 year study in a single hospital revealed incidence of Gram-negative pneumonia in 58% of bacteremia cases.19 The microbiology of pulmonary infections in neutropenic patients is frequently similar to that of hospital acquired pneumonia or ventilator associated pneumonia.

Following HSCT, patients continue to be at risk for bacterial pneumonia post engraftment of the stem cells, albeit less frequently. The risk factors for bacterial pneumonias during this period include the presence of acute or chronic graft versus host disease (GVHD) and the immunosuppressive therapy used to treat these patients. These patients are at risk of infection with encapsulated organisms such as S. pneumoniae and H. influenza. Gram-negative organism may be the etiology in up to 25% of patients.12

Since the introduction of Pneumococcal vaccine, there has been decreased incidence of penicillin resistant and invasive serotypes of Pneumococci. However, the incidence of other serotypes is still significant. In a single center study, Pneumococcal pneumonia was seen in 6.5% of patients. Increased incidence was noted in hematological malignancies versus solid tumors. Other risk factors noted were chronic obstructive pulmonary disease and diabetes mellitus. Most of these were healthcare associated infections.20

Empiric broad-spectrum antibiotics should be started immediately when bacterial pneumonia is suspected in patients with hematological malignancies. The American Thoracic Society guidelines for the treatment of healthcare associated pneumonia in patients with risk factors such as HSCT or neutropenia, recommend a regimen that includes antipseudomonal cephalosporin or carbepenem, or β-lactam, plus antipseudomonal fluoroquinolone or aminoglycoside, plus linezolid or vancomycin if methicillin resistant S aureus is suspected. In patients who develop bacterial pneumonia late following HSCT, coverage of encapsulated organisms with a fluoroquinolone is recommended. The antibiotic regimen should be narrowed if the etiologic agent is identified.21,22 Institutional resistance pattern needs to be considered when determining the choice of antibiotics.

Legionella pneumophila pneumonia is occasionally reported in patients with hematological malignancies. A study involving 49 patients with this infection reported that lymphopenia, systemic corticosteroids, and chemotherapy as the most common risk factors. It is identified using DFA (direct fluorescent antibody assay). Mortality can be as high as 31%.23 Macrolide or fluoroquinolone are the primary treatment. A prolonged course of antibiotics may be needed depending on the initial response to treatment.

Stenotrophomonas maltophilia is a growing concern. It is commonly seen in patients with obstructive lung disease, prolonged mechanical ventilation, recent broad-spectrum antibiotic exposure, and neutropenia.24 Lobar or lobular consolidation with absence of pleural effusion is common. Cavitation is rarely seen. Trimethoprim-sulfamethoxazole (TMP-SMZ) remains the preferred antibiotic in most patients. Ceftazidime, Moxifloxacin, Tigecycline, and Colistin are alternatives.

Nocardia infection has been rarely reported with an incidence ranging between 0.3 and 1.7%.25,26 The main predisposing factors include neutropenia, acute or chronic GVHD, and lack of prophylaxis with Trimethoprim-sulfamethoxazole. Fifty-six percent of the patients may have pulmonary involvement. The most common radiological findings include nodules with or without infiltrates, cavitation, and empyema. The diagnosis is usually made by Gram staining and modified acid-fast bacillus staining of sputum, bronchoalveolar lavage (BAL), or pleural fluid. Diagnosis can be further confirmed by CT-guided biopsy of pulmonary nodule or surgical lung biopsy. Coinfection with other organisms such as bacteria, Cytomegalovirus (CMV) and Aspergillus is common and may be seen in up to 36% of the patients.26

Treatment of Nocardia infection is by prolonged administration of TMP-SMZ. In case of an allergy or side effects associated with sulfa preparations, second line agents that are available include Amikacin, Minocycline, Cephalosporin, or Imipenem. Response to treatment is generally good, and long term survival in patients with nocardiosis is not significantly different from controls.26 The increased use of TMP-SMZ for prophylaxis against P. jiroveci has the added benefit of reducing the incidence of Nocardia infections.

Mycobacterium tuberculosis infection is rare in immunosuppressed patients and varies significantly depending on whether the patients lived in an endemic area. In a large cancer center in the United States, the overall rate of active M. tuberculosis infection was 0.2 in 1000 new cancer diagnoses. Five out of the 18 patients described had hematological malignancies and 4 were neutropenic.27 In India, a report of 130 patients with acute leukemia, 9 cases (6.9%) had active tuberculosis28.

The main risk factors for M. tuberculosis in patients with hematological malignancies are allogeneic transplantation, total body irradiation, chronic GVHD, corticosteroid therapy, and residence in endemic areas.29 The clinical and radiological picture is similar to disease in nonimmunosuppressed patients. However, atypical presentations such as lack of cavitation, rapidly progressive disease, and extra-pulmonary manifestations have been described. The diagnosis of infection is usually made by acid-fast bacillus staining and culture of sputum, BAL, or pleural fluid samples. Rapid diagnosis of M. tuberculosis may be established by polymerase chain reaction (PCR) test. It is important to check drug susceptibility on positive samples. Treatment is similar to patients without malignancies. Some studies suggest extending treatment to 1 year.30

Nontuberculous mycobacterial (NTM) infections are also rare in these patients. NTM infections include Mycobacterium avium complex, M. kansasii, and M. chelonae. In an epidemiological study of 2856 patients with hematological malignancies at a single center in Taiwan (a tuberculosis endemic area), the prevalence of NTM was about 1.2%.31 Nontuberculous mycobacteria may colonize the airways of the patients with chronic lung diseases such as bronchiectasis, which may create a challenge in determining the significance of isolating these bacteria from lower respiratory tract samples. The presentation ranges from mild worsening of obstructive lung disease, consolidation, nodules, cavity to disseminated disease.31 Mycobacterium avium intracellulare infection is treated with a regimen that includes Clarithromycin, Azithromycin, Ethambutol, Rifampin, and Rifabutin for 18 months (12 months after negative cultures).32,33

4. Fungal infections

Aspergillus species are ubiquitously found in the environment. They are regularly inhaled into the lower respiratory tract where they transform to short, acutely branching, and septate hyphae. Neutrophils and alveolar macrophages act as the primary defense mechanisms against infection by these organisms. Their activity is further augmented by T-helper cell induced cytokine production (such as TNF-α, interferon-γ, IL-12, and IL-15). As mentioned previously, neutropenia and defects in T-helper cell function also increase vulnerability to invasive disease by Aspergillus. Concomitant infection with Cytomegalovirus (CMV) in patients who underwent HSCT increases the risk of invasive pulmonary aspergillosis (IPA). The hazards ratio for IPA in this setting increases by 13.3-fold.34 A retrospective review conducted over a 9-year period, including 385 cases of patients with suspected and documented IPA, revealed that the disease-specific survival rate was 60%. Factors that predicted mortality were allogeneic HSCT, neutropenia, progression of the underlying malignancy, prior respiratory disease, corticosteroids therapy, renal impairment, low monocyte counts, pleural effusion, and disseminated aspergillosis.35

IPA usually affects the lower respiratory tract, but occasionally has been reported in extra-pulmonary sites like sinuses, gastrointestinal tract, and skin.3539 Patients usually present with symptoms consistent with bronchopneumonia that is unresponsive to antibiotics. In presence of vascular invasion, pleuritic chest pain and hemoptysis have been reported (due to small pulmonary infarcts). IPA is one of the most common causes of hemoptysis in neutropenic patients with cavitation.40 Patients may also present with seizures, meningitis, epidural abscess, intracranial hemorrhage, ring-enhancing intracranial lesions as result of hematogenous dissemination of the organism to the brain. Skin, kidneys, heart, esophagus, and liver are also occasionally involved.

Diagnosis of IPA in patients begins with identifying at-risk patients based on presence of risk factors. Histopathological diagnosis remains the gold standard for the diagnosis of IPA.41,42 The presence of septate, acute, branching hyphae, with invasion of native tissues, paired with positive culture from the same site, is diagnostic of IPA. The histopathological findings in neutropenic patients are characterized by scant inflammation, extensive coagulation necrosis associated with hyphal angioinvasion, and high fungal burden. Conversely, in patients with HSCT, there is intense inflammation with neutrophilic infiltration, minimal coagulation necrosis, and low fungal burden.43

The sensitivity and specificity of chest radiograph are low in early stages of the disease. Radiographic abnormalities may include pleural-based infiltrates, rounded opacities, or cavities. Pleural effusions are rare. HRCT has evolved as a useful tool for early diagnosis of IPA. Early implementation of this diagnostic modality has also been shown to favor improved outcomes in these patients.44,45 It is also a valuable tool in planning of further invasive diagnostic studies like bronchoscopy or surgical lung biopsy. The typical radiological findings include multiple nodules (Fig. 9.3), halo sign, air crescent sign. Halo sign, usually seen in first week, is mainly seen in neutropenic patients. It appears as a zone of low attenuation surrounding a central lesion of higher attenuation owing to hemorrhage around the lesion. Another classic and late radiological sign is the air crescent sign. The crescent-shaped lucency in the region of the original nodule occurs secondary to necrosis. Both the halo and the air crescent signs are neither sensitive nor pathognomic of IPA. In a large study of 236 patients with IPA, 61% of the cases had halo sign. On the other hand, the presence of halo sign portends a good prognosis, especially in patients with hematological malignancies.46


Figure 9.3 A and B are Chest CT Scan Views Showing Multiple Pulmonary Nodules, Some are Cavitating in a HSCT Patient With IPA.

The significance of isolating Aspergillus species in sputum samples depends on the immune status of the host. Studies have shown a positive predictive value of 80–90% in diagnosing IPA in immunosuppressed patients.4749 However, negative sputum studies have been noted in 70% of patients with confirmed IPA.49,50 Blood cultures are rarely positive in patients with IPA.

Bronchoscopy aids in direct visualization of the bronchial tree and in obtaining BAL for fungal staining, culture, Aspergillus antigen assays, and so on. It is specifically useful in patients with diffuse lung involvement. The sensitivity and specificity of BAL in diagnosis of IPA has been reported to be around 50 and 97%, respectively. However, the yield of BAL has also been reported to be lower.51 Transbronchial biopsies further carry increases the risk of bleeding without adding much to the diagnosis.

Aspergillus fumigatus is the most common cause of IPA. A review of 300 patients with proven IPA, identified Aspergillus terreus as the second most common species (23%). Infections by Aspergillus terreus were significantly more likely to be nosocomial in origin and resistant to Amphotericin B.52,53 The triazole antifungal agents have significantly better efficacy against Aspergillus terreus. An important part of diagnostic work up for IPA is distinguishing it from infections by other molds like Scedosporium spp., Pseudallescheria, and Fusarium, which may have similar histological appearance as Aspergillus. Hence, it is recommended to include the samples for culture when possible.

Galactomannan (GM) assay is an enzyme-linked immunosorbent (ELISA) based assay that is designed to detect GM, a polysaccharide cell-wall component of the Aspergillus. The Food and Drug Administration has approved its application to serum analysis with a threshold value of 0.5 ng/ml. It has been reported that the positive serum GM assay precedes clinical signs and radiographic changes by several days (5–8 days). It may also be useful in assessing the evolution of infection during treatment.54,55

A study by Pfeiffer et al., which included 27 studies from 1996–2005 of patients with IPA (defined according to the European Organization for Research on Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria), found that serum GM assay to have a sensitivity of 71% and specificity of 89%. The negative predictive value and positive predictive value were 92–98% and 25–62%, respectively.55

GM is found in certain food items, β-lactam antibiotics (eg, Piperacillin-Tazobactam), which may contribute to false positive results. The assay itself is species specific, and cannot exclude the concomitant infections by other molds such as Fusarium, Zygomycetes, and dematiaceous fungi.

There is accumulating evidence that GM assay may be applicable to body fluids such as BAL, urine, and cerebrospinal fluid. A prospective study of 200 patients with hematological malignancies and profound neutropenia, found that BAL–GM assay had sensitivity of 100% for IPA compared to serum GM assay.56 Musher et al. showed that incorporating GM assay and quantitative-PCR assay into standard BAL fluid analysis may enhance identification of Aspergillus species in patients with hematological malignancies57. Factors affecting GM assay in BAL samples was studied by Racil et al. In their study, the sensitivity and specificity of BAL–GM assay was reported to be 78% and 98%, respectively, when combined with serum and bronchial samples. The factors affecting its performance were noted to be neutropenia, BAL standardization and antifungal therapy.58 Adherence to standard BAL collection technique is paramount for ensuring reliability of the assay findings.

PCR is another tool available for the detection of Aspergillus DNA in BAL fluid and serum. The sensitivity has been reported to be between 67% and 100%, and specificity between 55% and 95%.59 However, the test alone cannot discriminate between colonization and infection. Rienwald et al. conducted the first multicenter, randomized control trial in which they elucidated that combining PCR assay with BAL–GM assay, resulted in sensitivity of 55% and specificity of 100%, respectively. Thus combining the two assays increased the specificity of diagnosing Aspergillus without the need for increasing the threshold cut-off value of GM assay, at the cost of sensitivity, to achieve the same specificity.60 The availability of Aspergillus PCR assay is still restricted to highly specialized laboratories.

Detection of serum (1→3)-β-d-glucan, a fungal cell wall constituent has been reported to be a highly sensitive and specific test for invasive deep mycosis, including candidiasis, fusariosis, pneumocystosis and aspergillosis, and could be useful in the immunosuppressed patients. A meta-analysis that included 15 studies, showed the sensitivity and specificity to be 76% and 85%, respectively. Combining with GM assay increased its specificity to 98% for diagnosing IPA. It also showed higher specificity with two consecutive positive results and in patients with hematological malignancies.61

The previous assays do not replace the value of clinical signs and radiological data in diagnosing IPA. They solely act as adjunctive data in helping to reach to the diagnosis.

The EORTC/MSG has provided its criteria for the diagnosis of invasive fungal infections (Table 9.1). These criteria are not necessary to consider treatment in clinical practice, rather they are put forward to guide clinical and epidemiological research.

Table 9.1

Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Criteria for the Diagnosis of IPA

Category Criteria
Proven IPA
1. Microscopic analysis on sterile material: histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or sterile biopsy in which hyphae are seen accompanied by evidence of associated tissue damage.

2. Culture on sterile material: recovery of Aspergillus by culture of a specimen obtained by lung biopsy.

Probable IPA

All 3 criteria

1. Host factors—1 of the following

a. Recent history of neutropenia (<500 neutrophils/mm3) for >10 days

b. Receipt of an allogeneic stem cell transplant

c. Prolonged use of corticosteroids >/= 0.3 mg/kg/d of prednisone equivalent for >3 weeks

d. Treatment with other recognized T-cell immunosuppressants

e. Inherited severe immunodeficiency

2. Clinical features—1 of the following 3 signs on CT

a. Dense, well-circumscribed lesion(s) with or without a halo sign

b. Air crescent sign

c. Cavity

3. Mycological criteria 1 of the following

a. Direct test (cytology, direct microscopy, or culture) on sputum, BAL fluid, bronchial brush indicating presence of fungal elements or culture recovery Aspergillus spp.

b. Indirect tests: galactomannan antigen detected in plasma, serum, or BAL fluid.
Possible IPA Host factors and clinical features. No mycological evidence

The mortality rate of IPA remains high despite initiation of treatment. Treatment should be considered as soon as there is a clinical suspicion for IPA. Prior to introduction of Voriconazole to clinical practice, Amphotericin B was the first line of therapy for IPA. The recommended dose is 1.0–1.5 mg/kg/d. Amphotericin B has serious side-effects including nephrotoxicity, electrolyte disturbances, and hypersensitivity. The lipid-based preparations of Amphotericin B (eg, liposomal Amphotericin B and lipid complex Amphotericin B) have relatively milder side effects. Voriconazole is a broad-spectrum triazole that is currently the treatment of choice for IPA, due to its fungicidal action. In a large prospective, randomized, multicenter trial, comparing Voriconazole to Amphotericin B as the primary therapy for IPA. Voriconazole treatment arm had a higher favorable response rate at week 12 (53% compared with 32% in patients receiving Amphotericin B), and a higher 12-week survival (71% compared with 58%).62 Voriconazole is available in both intravenous and oral formulations. The recommended starting dose is 6 mg/kg twice daily intravenously, followed by 4 mg/kg/d. Maintenance treatment can be considered after 1 week at 200 mg orally twice daily. The most frequent adverse effects of Voriconazole include visual disturbances described as blurred vision, photophobia, and altered color perception. Liver function test abnormalities and skin reactions are less common side effects.

Posaconazole is another broad-spectrum triazole that is available as an oral and intravenous (recent) formulation. Currently, it is used as salvage therapy in patients with invasive aspergillosis refractory to treatment with Voriconazole or lipid formulation Amphotericin B or in patients who are intolerant to its adverse effects of these medications.63

Recently, the FDA has approved the use of Isavuconazonium sulfate, a broad-spectrum triazole for treatment of IPA. A phase III trial involving 516 patients compared Isavuconazole to Voriconazole in treatment of patients with invasive aspergillosis. Isavuconazole was found to be noninferior to Voriconazole for all-cause mortality.64 It is reported to have slightly lower incidence of adverse effects. Most common adverse effects are gastrointestinal disorders, hypokalemia, and elevated liver enzymes.

Echinocandin derivatives such as Caspofungin, Micafungin, and Anidulafungin are effective agents and can be considered in the treatment of IPA refractory to first line agents or if the patient could not tolerate first line agents.65 The Infectious Disease Society of America recommends Voriconazole as the primary treatment for IPA, and liposomal Amphotericin B as an alternative regimen. For salvage therapy, agents include lipid-based preparations of Amphotericin B, Posaconazole, Itraconazole, Caspofungin, or Micafungin.66

The role of surgical resection although limited, is indicated in cases of massive hemoptysis, or lesions close to the great blood vessels or pericardium, or the resection of residual localized pulmonary lesions in patients with continuing immunosuppression.

Immunomodulatory therapy has been considered to decrease degree of immunosuppression in order to aid in treatment of IPA. Colony stimulating factors such as granulocyte-colony stimulating factors (G-CSF) or interferon-γ have been used. However, current evidence to their use is limited to few randomized studies and case reports. In one such randomized study that included patients receiving chemotherapy for leukemia, prophylactic therapy with GM-CSF led to a lower frequency of fatal fungal infections compared with placebo (1.9% vs 19% respectively) and reduced overall mortality.67

Due to high mortality related to invasive aspergillosis, prophylaxis remains an important part of management of patients with risk factors. Patients should be advised to avoid construction areas. Similarly, use of high-efficiency particulate air (HEPA) filtration with or without laminar airflow ventilation is efficient in protecting against IPA. Itraconazole was shown to be effective in preventing fungal infections in neutropenic patients, according to a metaanalysis.68 Posaconazole has also been shown to be effective prophylactic agent in high risk patients with acute myelogenous leukemia, myelodysplastic syndrome, and GVHD after allogeneic HSCT.

In a Centers for Disease Control sponsored surveillance program for invasive fungal infections that included 886 patients with invasive fungal infection, non-aspergillus mold were responsible for 14% of infections. In addition, Cryptococcus infection was found in 4%, endemic fungi like Coccidiomycoses, Blastomyces, Histoplasma in 3%, and Pneumocystis in 2% of patients.69

Hyaline hyphomycetes such as Fusarium and Scedosporium spp. are the main non-aspergillus molds that are reported in patients with hematological malignancies. These organisms resemble Aspergillus and culture is the only means to distinguish these organisms. Lung is the primary site of infection however they may disseminate to other sites. Corticosteroid therapy and neutropenia are common risk factors. The mortality in patients with pulmonary Fusariosis is as high as 65% within one month of diagnosis.70 Scedosporium has been isolated from the air in hospitals. Patients usually present with thin wall cavities or nodules. Air crescent sign may be present or absent. The patient’s history usually denotes that these lesions are refractory to antibiotics and antifungal therapy. The diagnosis is confirmed by isolating the organisms by culture either in blood, BAL or lung tissue. Mortality associated with these fungal infections remains very high, in the range of 70–100%.71

Zygomycetes such as Rhizopus and Mucor are characterized by sparsely septate, broad hyphae with irregular branching. They have a predilection to invade blood vessels with associated tissue destruction due to thrombosis and necrosis. They usually involve the sinopulmonary tree and dissemination to other organs is rare. Although, they are an uncommon cause of invasive fungal infection in immunosuppressed patients (0.5–1.9%), mortality usually reaches 80%.72

Cryptococcal infections have been reported to be low due to the widespread use of Fluconazole prophylaxis in patients with hematological malignancies. Patients with profound T-cell depression are at highest risk. The diagnosis of pulmonary cryptococcosis is made by detection of the fungus in BAL or lung tissue samples. The sensitivity and specificity of serum cryptococcal antigen assay is more than 95%. The treatment includes Fluconazole or Itraconazole in milder cases, with use of Amphotericin B in severe cases. Either Fluconazole or Itraconazole is used for maintenance therapy.73

Invasive Candida infection develops in 11–16% of patients with hematological malignancies. Autopsy studies suggest that 50% of infected patients have pulmonary involvement.74 Pulmonary infection results from dissemination of invasive candidiasis or candidemia. In a study of 529 patients who died from leukemia or myelodysplastic syndrome and were affected by candidiasis, 45% had lung involvement.75 Primary Candida pneumonia is extremely rare. Histopathological confirmation is necessary in most of the cases. Previous triazole antifungal exposure, renal failure, neutropenia have been associated with higher mortality rates. Lately, there has been a shift in the candida species from C. albicans to more resistant species such as C. glabrata or C. krusei.

Pneumocystis jirovecii pneumonia is caused by inhalation of the aerosolized organisms. Previously, the incidence of Pneumocystis pneumonia was up to 20% of patients with hematological malignancies.76 However the routine prophylaxis with TMX/SMZ has significantly decreased this number. Patients with lymphoproliferative disorders appear to be at highest risk for P. jiroveci infection followed by patients treated with the prolonged administration of high dose corticosteroid therapy and purine analogues such as Fludarabine.7779

P. jirovecii pneumonia presents with acute onset, rapidly progressing symptoms of dyspnea, nonproductive cough, and fever. Hypoxemia is usually significant in these patients. Radiologically, there are perihilar interstitial or alveolar infiltrates (Fig. 9.4). Ground glass opacities are seen on HRCT of chest. Lactate dehydrogenase (LDH) levels may be elevated. The diagnosis is usually done on BAL analysis. The sensitivity of this test may be lower than patients with HIV infection due to lower organism burden. Similarly, induced-sputum samples are useful.80,81


Figure 9.4 Reconstructed Chest CT Scan Image Showing Bilateral Pulmonary Infiltrates in a Patient With Acute Myeloid Leukemia and P. jirovecii Pneumonia

Mortality has been recently reported to be 20% of patients with malignancy. The need for mechanical ventilation portends poor outcome82. Prophylaxis using TMP-SMZ is recommended for patients who are on chronic corticosteroid therapy and following engraftment in allogeneic HSCT recipients for 100 days. However, if a patient has chronic GVHD, then prophylactic treatment is continued as long as the patient is on immunosuppressive therapy.

Endemic mycoses such as Histoplasmosis, Blastomycosis, and Coccidiomycosis are rare in patients with hematological malignancies.83 These infections tend to have geographical distribution, and are usually caused by endogenous reactivation of a latent infection. Initial treatment is with high dose Amphotericin B. After controlling the infection, Itraconazole or Fluconazole can be used as a maintenance treatment.

5. Cytomegalovirus

CMV infection is an important infection in immunosuppressed patients, especially in posttransplant patients. The predominant site of infection being the gastrointestinal system, however, up to one-third of patients with HSCT may have pulmonary involvement. The incidence of CMV pneumonia has been noted to be around 3.5% prior to 1997, which has since decreased to 0.8%.84 The risk of developing CMV pneumonia has been noted to increase with use of T-cell depleting chemotherapy (such as fludarabine, Alemtuzumab, Cytarabine, or high dose cyclophosphamide and corticosteroids), which are used to treat leukemia and lymphoma. It has also been reported in allogeneic HSCT transplant, specifically in seropositive recipients. The risk is least when both donor and recipient are seronegative.85

CMV pneumonia presents clinically with acute onset fever, dyspnea, nonproductive cough and pleurisy. The patient may further progress to acute hypoxemic respiratory failure in matter of 2 weeks. Chest imaging may show interstitial pattern of pneumonia or patchy consolidation. HRCT of chest is more sensitive in identifying ground glass opacities, nodular opacities, diffuse or patchy in distribution, and thickening of the interlobular septae. Pleural effusion is also seen in up to 25% of these patients.86

The classic histopathological finding of CMV pneumonia is the presence of intracytoplasmic eosinophilic inclusion bodies within the areas of mononuclear, interstitial inflammation on lung biopsy. However, they may be absent early in the disease. These findings may be associated with alveolar epithelial desquamation and hyaline membrane formation. Demonstration of inclusion bodies in the alveolar epithelial cells on cytological examination of the BAL fluid has specificity of 98% for CMV pneumonia, but has low sensitivity, with positive predicted value of 73%.87. Rapid culture of the BAL fluid using shell viral technique is highly sensitive (99%) in detecting the virus. On the other hand, it cannot differentiate between viral shedding and invasive disease and, hence, is less specific (67–83%).87 CMV pp65 antigen assay is based on detection of pp65 antigen in blood neutrophils and as such, its use is limited in neutropenia. However, it is useful in monitoring treatment response. Persistence of antigenemia despite 2 weeks of therapy may suggest antiviral resistance. CMV PCR analysis is a quantitative analysis of viral DNA that is shed in body fluids including blood, urine, cerebrospinal fluid, and alveolar lavage. Detection of viral DNA in alveolar lavage is diagnostic of CMV pneumonia, but is associated with frequent false positivity.88 Clinicians are often confronted with positive laboratory results, and it is vital to correlate clinical, radiological features with a positive result in order to reliably diagnose CMV infection.

Ganciclovir is currently the standard of treatment for CMV pneumonia. Mortality has been shown to decrease if treatment is initiated prior to onset of respiratory failure. Ganciclovir prophylaxis has also shown reduction in CMV invasive disease and mortality in HSCT patients.89 It is administered in seropositive patients and in seronegative recipient with a seropositive donor. Prophylaxis is initiated 5 days before engraftment and continued for 100 days after transplantation.

6. Community respiratory viruses

There is limited data on the significance of community respiratory infections in immunosuppressed patients due to seasonal and endemic nature of these infections and possibly due to presence of mild or no symptoms in most of the cases. Commonly identified viruses that may cause serious infections in these patients are respiratory syncytial virus (RSV), parainfluenza, influenza, and adenovirus. In a retrospective analysis of 306 patients with 343 episodes of viral infections, 33% were from Influenza, 31% from RSV and 27% from Parainfluenza (mainly type 3). About one-third of these patients progressed to having lower respiratory tract infections. High risk patients were identified as age >65 years, severe neutropenia and lymphopenia and allogeneic HSCT. Overall, mortality was 15%.90

In lower respiratory tract infections, HRCT of the chest may show patchy ground glass opacities, nodules, bronchial wall thickening or combination of earlier. Pleural effusions are less common. Rapid laboratory diagnosis can be made using direct-(DFA) and indirect-(IFA) fluorescent antibody assays, performed on nasopharyngeal swabs or wash. Sensitivity ranges between 20–52%.91 Viral cultures usually take 7–14 days to be reported. BAL fluid may also be useful in patients with lower respiratory tract infections. Coinfections with bacteria, P. jiroveci, or fungi are commonly seen and these infections should be excluded by the appropriate diagnostic studies.

Infections due to respiratory viruses are usually self-limiting, although lower respiratory infections leading to acute respiratory failure are associated with high mortality. Simple measures such as hand washing, early isolation of patients suspected to have infection, limiting visitors during endemic seasons, and restricting patient contact with symptomatic healthcare personnel or visitors are very effective preventative measures against these infections.

7. Conclusions

Immunosuppression due to abnormalities in the human’s defense mechanisms is common and is associated with a variety of malignant and nonmalignant conditions. Immunosuppressed patients are prone to unique respiratory infections. In recent years there have been important advances in the diagnosis and management of these infections. However, there remains significant challenges and unacceptably high mortality. More research is needed to prevent and minimize the severity and duration of immunosuppression. It is also important to better identify risk factors for these infections. More robust, less invasive diagnostic tests with high sensitivity and specificity are needed. On the other hand, there is still demand for better tolerated and more effective therapeutic agents. The field of respiratory complications in immunosuppressed patients is an exciting one and all indications are that the future will hold more success.


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