Pneumonia in an Immunocompromised Patient

Etiology

Common causes of pulmonary infections in the general population, such as Influenza A and B viruses, Streptococcus pneumoniae, Mycoplasma pneumoniae, and Haemophilus influenzae, are also common in immunocompromised individuals. Besides the common pathogens capable of infecting an immunocompetent individual, immunocompromised patients are also at risk of infection from opportunistic pathogens.

Patients with defective humoral immunity are at increased risk of infection from encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae. Those with neutropenia are predisposed to infections from S. aureus, Gram-negative bacilli (including Pseudomonas aeruginosa), as well as fungi such as Aspergillus spp. Impaired T-cell immunity can lead to a range of infections from:

• Viruses, such as Cytomegalovirus
• Intracellular bacteria, for example, Legionella
• Acid-fast bacteria such as Mycobacteria and Nocardia
• Fungi, such as Pneumocystis jirovecii, Aspergillus spp., Coccidioides immitis, Cryptococcus spp., Blastomyces dermatitidis, Histoplasma capsulatum, etc [3]

Latent tuberculosis may also reactivate as immunodeficiency increases. Pneumocystis jirovecii is another common opportunistic fungal pathogen that infects the lungs in the immunocompromised, especially in those with AIDS. The type of pathogens involved in pulmonary infections in patients with AIDS is dependent on the CD4 count of the patient. Typical bacterial infections are common in patients with a CD4 count above 500 cells per cubic millimeter, whereas opportunistic infections occur more commonly as the CD4 count drops below 200 cells per cubic millimeter.

Bacteria such as S. aureus, P. aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia complex, are the most common pathogens involved in pulmonary infections immediately after solid organ transplantation, especially heart and lung. ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) especially cause pulmonary infections after lung transplant. Due to the immunosuppression, infections from other opportunistic pathogens such as Cytomegalovirus (CMV) can also occur after solid organ transplantation. In the early phase following hematopoietic stem cell transplantation (HSCT), the majority of pulmonary infections are due to bacteria, for example, S. pneumoniae, Klebsiella, Gram-negative bacilli, and S. aureus. Up to three weeks following HSCT, which is the neutropenic phase, fungi, especially Aspergillus spp. are a common cause of infections, while CMV infections can occur up to three months following HSCT. Pneumocystis pneumonia (PCP) is uncommon after HSCT except in the setting of graft-vs-host disease.[2][3] Following allogeneic cell transplantation, pulmonary infections due to Fusarium species can also occur, which are seen exclusively in the severely immunocompromised.[4]

Epidemiology

The estimated U.S population, which is immunocompromised due to any cause (HIV/AIDS, chemotherapy, immunomodulatory drugs, etc.), is 2.7%, which is roughly 8 million people.  Among these, immunodeficiency is found to be highest in women, Whites, and people aged 55 to 59.[5] Moreover, it is estimated that 1.1 million people in the United States are infected with HIV, the primary virus leading to acquired immune deficiency syndrome (AIDS). Worldwide, 36.9 million people are estimated to be infected with HIV. HIV infection rate is found to be highest among men who have sex with men, IV drug users, sex workers, transgender people, and incarcerated populations.[6][7]

More than 5 million cases of community-acquired pneumonia occur every year in the U.S. and the incidence rates are highest among males and African-Americans.[8]

More than 400,000 cases of Pneumocystis jirovecii pneumonia (PCP) occur annually in patients with AIDS throughout the world. A majority of these are either patients who have an undiagnosed HIV infection or those receiving inadequate antiretroviral therapy. On the other hand, the global incidence of PCP in non-HIV infected individuals is more than 100,000 annually. In these non-HIV infected, yet immunocompromised individuals, the most common conditions and risk factors are:

• Hematological malignancies, with corticosteroids, monoclonal antibodies, and T-cell dysfunction being the main risk factors.
• Solid tumors, high dose chemotherapy, prolonged corticosteroid use, marrow transplantation are the biggest risk factors in this population.
• Solid-organ transplantation, with decreased CD4+ count being the main risk factor.
• Autoimmune diseases, especially in patients receiving anti-TNF alpha and other immunomodulatory drugs (the biggest risk factor for PCP in this population).
• Patients receiving glucocorticoids or other biological and immunomodulatory drugs for any other condition.[9]

Opportunistic fungal infections such as Histoplasma capsulatum and Coccidioides immitis occur primarily in endemic regions, such as the Ohio and Mississipi river valleys and Southwestern U.S, respectively.[10][11]

Pathophysiology

As the respiratory tract is constantly exposed to the environment, it is not sterile.[3][8] Moreover, prolonged use of antibiotics for prophylaxis and treatment of other infections, along with frequent hospital exposure, use of corticosteroids, and low CD4 counts increase the frequency of airway colonization by various pathogens in immunocompromised patients.[12] This is thought to be responsible for altering the microbiota of the respiratory tract. This colonization and alteration of the respiratory tract microbiome can lead to dysbiosis and further impairment of immune surveillance, resulting in a state which is supportive of the growth of pathogens in the lower airway.[13] As the individual’s immunity decreases, latent pulmonary infections such as tuberculosis turn into active infections as well.[14][15][16]

For the pathogen to cause pneumonia, it must reach the alveolar space and have a large enough inoculum, or overwhelm the host’s already impaired immune system. Uncontrolled multiplication by the pathogen in the alveolar spaces triggers the macrophages to bring about an inflammatory response. Cytokines released due to the inflammatory response are responsible for the clinical manifestation of pneumonia. For example, interleukin-1 (IL-1) and tumor necrosis factor (TNF) are responsible for fever while interleukin-8 (IL-8) and colony-stimulating factors cause chemotaxis and neutrophil maturation culminating in leukocytosis. This inflammatory response also results in leakage of the alveolar-capillary membranes, which leads to decreased lung compliance and shortness of breath.[8][16] In the case of viral pneumonia, the target cells are pneumocytes. This results in alveolar damage, which initiates a cell-mediated inflammatory response leading to alveolar capillary membrane leakage, edema, and microhemorrhage.[17]

History and Physical

The clinical features of pneumonia in immunocompromised patients depend on the infective organism. Pneumonia due to common bacterial pathogens, such as S. pneumoniae, has typical features of pneumonia similar to what is seen in immunocompetent individuals. The presentation is usually acute, and patients have a cough that can be productive of purulent, mucoid, or blood-tinged sputum. Along with this, fever, shortness of breath, and fatigue are also common symptoms.

Opportunistic infections may have a more subacute to chronic course. The presenting symptoms again depend on the infective organism.

In HIV-infected patients, Pneumocystis pneumonia (PCP) has a sub-acute onset, associated with low-grade fever, dry cough, and progressive dyspnea. However, in HIV-uninfected immunocompromised patients, PCP has a more acute presentation. In these patients, a high-grade fever, along with fulminant respiratory failure is seen.[9]

Pulmonary tuberculosis has a chronic course. There is low-grade fever, which can increase as the disease progresses. Patients usually have weight loss, and also complain of malaise, and night sweats. The cough, which is mild and non-productive initially, can progress to become more frequent and productive of yellow-green or blood-streaked sputum. As the disease progresses, there may be frank hemoptysis along with dyspnea.[18][19]

Cytomegalovirus pulmonary infection, especially in lung transplant patients, can cause a low-grade fever, non-productive cough, and dyspnea.

The physical examination findings of pneumonia are not specific for any organism or disease. Some of them are:

• Fever
• Increased respiratory rate
• Dullness of percussion notes
• Crepitation, rhonchi, and bronchial breath sound on auscultation
• Altered mental status, especially in the elderly
• Hypotension, especially in patients with sepsis

Evaluation

A carefully collected history and thorough physical examination lay the foundation for a diagnosis. They also help decide on which investigations to carry out. The provider should inquire about any history of malignancy, organ transplantation, use of corticosteroids, or any condition necessitating prolonged immunosuppressive drugs, intravenous drug use, and the patient’s sexual practices to find out the cause of immunodeficiency. The history and physical examination findings will also give clues towards the probable etiology of the disease.

Routine laboratory investigations should be ordered, which include:

• Complete blood count (CBC) with differential. In the case of bacterial etiology, leukocytosis, along with the raised neutrophil count, might be seen, provided the patient does not have immunodeficiency due to neutropenia. In the case of viral pneumonia, the leukocyte count can be elevated, decreased, or normal.
• Inflammatory markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and procalcitonin will be raised due to ongoing inflammation. Procalcitonin and CRP can also help predict the severity of pneumonia and prognosis early on in the disease.
• A chemistry panel will help in determining the patient’s hydration status.
• Sputum smear and culture should be obtained, if possible. Bronchoalveolar lavage (BAL) may have to be performed in case of inadequate sputum production, for example, in the case of PCP or tuberculosis. A transbronchial lung biopsy can also be performed to reach a definitive diagnosis.
• Blood cultures should be obtained before initiating any antibiotics.
• CD4 count should be done in patients with HIV.

Imaging modalities for evaluation of pneumonia include:

• Chest X-ray (CXR). This is the first-line imaging of choice in the evaluation of a suspected case of pneumonia. Posteroanterior (PA) and lateral radiographs should be obtained. However, CXR may be normal for up to 72 hours in immunocompromised patients despite having symptoms.
• Computed tomography (CT) of the chest should be obtained in patients with high suspicion of pneumonia and normal findings on CXR. In neutropenic patients, CXR will have minimal or no abnormalities and so performing a CT scan is highly recommended.

Other investigations for specific etiologies include:

• Urine antigen testing for pneumococcus and Legionella
• ELISA and PCR for viruses such as Herpes Simplex Virus (HSV), Influenza A and B, and Cytomegalovirus (CMV)
• Serum antigen testing for Cryptococcus and Aspergillus
• Beta-D-glucan testing if a fungal pathogen is suspected.[2][8][17][20]

Treatment / Management

Management of pneumonia in immunocompromised patients consists of preventing pneumonia in the first place, and treatment of pneumonia if it has occurred.

In HIV-infected patients, antiretroviral therapy plays an important role in preventing opportunistic infections. Prophylaxis against some common opportunistic lung infections is as follows:

• Transplant candidates should receive the 13-valent pneumococcal conjugate vaccine (PCV13), and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) as pneumococcal pneumonia is a common infection after organ transplantation. Likewise, HIV-infected individuals should also receive vaccination against Pneumococcus. 
• Annual inactivated intramuscular influenza vaccine.[21]
• Screening for latent tuberculosis should be done in all HIV-infected patients regardless of CD4 counts.
• Trimethoprim-sulfamethoxazole (TMP-SMX) for PCP. In HIV-infected patients, this should be initiated when CD4 counts fall below 200 cells per cubic millimeter.[9] TMP-SMX also provides some degree of prophylaxis against Nocardia.
• In solid organ transplant recipients who are at increased risk of CMV reactivation (e.g., seropositive recipient, or seropositive donor), ganciclovir or valganciclovir is used for prophylaxis.[22][23]
(A1)

For the treatment of pneumonia, a risk assessment should be done to decide if the patient can be treated in the outpatient, regular inpatient (non-ICU), or intensive care unit (ICU) setting. Risk assessment scores such as the pneumonia severity index and the CURB-65 score are helpful, and markers of inflammation such as CRP or procalcitonin can further aid in this regard.[24]

Empiric antimicrobial therapy should be started as soon as possible. Some empiric antimicrobials of choice are:

• Trimethoprim-sulfamethoxazole (TMP-SMX) if Pneumocystis pneumonia is suspected. Moreover, glucocorticoids should be added if the patient’s partial pressure of oxygen is less than 70 mmHg, alveolar-arterial (A-a) gradient is equal to or more than 35 mmHg or oxygen saturation is less than 92% on room air.
• Ganciclovir or valganciclovir for CMV.
• Antipseudomonal antibiotics, eg, piperacillin-tazobactam, cefepime, cefoperazone, fluoroquinolones (except for moxifloxacin), carbapenems (except for ertapenem), etc. 
• For the treatment of community-acquired pneumonia (CAP) in the outpatient setting, beta-lactam antibiotics such as amoxicillin, with or without a macrolide or doxycycline.
• For inpatient (non-ICU) patients with CAP, a beta-lactam (e.g., ceftriaxone) plus a macrolide, or monotherapy with a fluoroquinolone (e.g., levofloxacin) may be used. Coverage for methicillin-resistant S. aureus (MRSA) and Pseudomonas should be included (e.g., vancomycin and cefepime, respectively).
• For pneumonia in the ICU setting, a beta-lactam (e.g., ceftriaxone) plus azithromycin or levofloxacin, along with vancomycin for MRSA coverage, and anti-pseudomonal coverage (e.g., imipenem or piperacillin-tazobactam) are used.
• Azole antifungals (e.g., fluconazole, voriconazole) if a fungal etiology, such as Histoplasma, is suspected. Voriconazole is especially effective against Fusarium and Aspergillus.
• A combination of rifampin, isoniazid, ethambutol, and pyrazinamide is used for the treatment of active tuberculosis.

The final choice of antimicrobial should be directed by the results of the culture and sensitivity report. 

Besides antimicrobial therapy, other measures can include:

• Discontinuation of immunosuppressive therapy if possible
• Chest physiotherapy
• Ventilatory support if the patient is in respiratory distress
• Early mobilization

Differential Diagnosis

The differential diagnoses for pneumonia in immunocompromised patients include:

• Aspiration pneumonia
• Acute respiratory distress syndrome
• Bronchitis
• Lipoid pneumonia
• Pulmonary edema
• Pulmonary alveolar proteinosis
• Lymphocytic interstitial pneumonia
• Graft-vs-host disease
• Lymphoma
• Kaposi sarcoma

Prognosis

The prognosis of pneumonia in immunocompromised individuals depends on several factors, some of which are:

• Age
• Type and degree of immunocompromise
• Associated comorbidities, for example, diabetes, heart failure, chronic kidney disease, malignancy, etc
• Severity of illness
• The setting of care, i.e., outpatient vs. inpatient (non-ICU) vs. ICU
• Drug resistance of the infective organism

Scoring systems such as the CURB-65 and the pneumonia severity index (PSI) have been developed to predict the prognosis in pneumonia patients in general; however, they are limited in their usefulness in immunocompromised patients.[25] Inflammatory markers such as CRP, IL-6, or procalcitonin can also be used in adjunct to the PSI or CURB-65 scores to get a more accurate idea of illness severity and prognosis.[24]

Complications

Some of the potential complications are:

• Empyema
• Lung abscess
• Superinfection
• Acute respiratory distress syndrome
• Sepsis
• Metastatic infections to other organs
• Respiratory failure
• Multiorgan failure
• Exacerbation of preexisting conditions, such as heart failure
• Development of drug resistance in infective organisms
• Drug toxicity