Immunocompromised patients have an impaired immune system leading to decreased resistance to infections. The immunocompromise can be innate; however, acquired immunodeficiency is far more common due to the recent advances in cancer chemotherapy, hematopoietic stem cell and solid organ transplantation, use of immunomodulatory drugs and AIDS. These recent developments have led to an increase in the number of immunocompromised patients. Pulmonary infections are quite common in immunocompromised patients owing to the respiratory tract’s constant environmental exposure. Besides the common pathogens capable of infecting an immunocompetent individual, immunocompromised patients are also at risk of infection from opportunistic pathogens. The type of pathogen involved and the severity of infection depend on the type, duration, and degree of immunodeficiency. Types of common immunodeficiencies are:
It is important to remember that various infections can be present simultaneously in an immunocompromised patient.[1][2][3]
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:
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 3 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 3 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]
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 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. 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:
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]
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][13][14][15] 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.[16] As the individual’s immunity decreases, latent pulmonary infections such as tuberculosis turn into active infections as well.[3]
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][15] In the case of viral pneumonia, the target cells are pneumocytes. This results in alveolar damage, which initiates a cell-mediated inflammatory response. Alveolar capillary membrane leakage, edema, and microhemorrhage ensue.[17]
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:
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 physician 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:
Imaging modalities for evaluation of pneumonia include:
Other investigations for specific etiologies include:
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:
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:
The final choice of antimicrobial should be directed by the results of the culture and sensitivity report.
Besides antimicrobial therapy, other measures can include:
The differential diagnosis can include
Prognosis of pneumonia in immunocompromised depends on several factors, some of which are:
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]
Some of the potential complications are:
Following consultations should be considered:
To prevent pneumonia in immunocompromised individuals, the following are recommended:
Patients with weakened immune defenses are particularly susceptible to developing pneumonia rapidly. It is for this reason that high clinical suspicion and detailed history taking is required at the initial evaluation. An interprofessional team approach is needed in the management of pneumonia in immunocompromised patients.
The most valuable treatment outcome for patients is treating the underlying infection. Close follow up as outpatient with treatment plan compliance is essential in preventing recurrence. For transplant patients, close monitoring and re-evaluation of immunosuppressive drugs are essential. Close coordination with a respiratory therapist is essential to ensure optimal oxygen delivery. Nursing care is just as important and can prevent unnecessary complications like pressure ulcers. These patients also need dietary consult and physical therapy to maintain a healthy muscle mass and maintain some degree of immunity
With evaluation across multiple disciplines, a team approach, and early intervention, positive outcomes can be achieved.
Outcome
Pneumonia is associated with significant mortality, both in the short and long term, in the general population. In one study, it was found to be associated with a mortality of 6.5% during hospitalization, and a mortality of 13%, 23.4%, and 30.6% at 30 days, 6 months, and 1 year, respectively.[26] [Level 4] Overall community-acquired pneumonia mortality can be from 5% to greater than 30% and is greatest with associated leukopenia and neoplastic disease.[27] [Level 4]
Untreated Pneumocystis pneumonia is associated with a mortality of 90% to 100%. 1079469 In HIV infected patients with PCP, mortality was found to be 6.6% overall, and 50-60% in patients who were intubated. In non-HIV infected immunocompromised patients with PCP, the overall mortality was 39%, and 66% among intubated patients.[28] [Level 4]
[1] | Skřičková J, [Pneumonia in immunocompromised persons]. Vnitrni lekarstvi. Winter 2018; [PubMed PMID: 29303280] |
[2] | Franquet E, Pneumonia. Seminars in roentgenology. 2017 Jan; [PubMed PMID: 28434501] |
[3] | Letourneau AR,Issa NC,Baden LR, Pneumonia in the immunocompromised host. Current opinion in pulmonary medicine. 2014 May; [PubMed PMID: 24626236] |
[4] | Nucci F,Nouér SA,Capone D,Anaissie E,Nucci M, Fusariosis. Seminars in respiratory and critical care medicine. 2015 Oct; [PubMed PMID: 26398537] |
[5] | Harpaz R,Dahl RM,Dooling KL, Prevalence of Immunosuppression Among US Adults, 2013. JAMA. 2016 Dec 20; [PubMed PMID: 27792809] |
[6] | World AIDS Day - December 1, 2018. MMWR. Morbidity and mortality weekly report. 2018 Nov 30; [PubMed PMID: 30496156] |
[7] | Deeks SG,Overbaugh J,Phillips A,Buchbinder S, HIV infection. Nature reviews. Disease primers. 2015 Oct 1; [PubMed PMID: 27188527] |
[8] | Sattar SBA,Sharma S, Bacterial Pneumonia 2020 Jan; [PubMed PMID: 30020693] |
[9] | Cillóniz C,Dominedò C,Álvarez-Martínez MJ,Moreno A,García F,Torres A,Miro JM, {i}Pneumocystis{/i} pneumonia in the twenty-first century: HIV-infected versus HIV-uninfected patients. Expert review of anti-infective therapy. 2019 Oct; [PubMed PMID: 31550942] |
[10] | Horwath MC,Fecher RA,Deepe GS Jr, Histoplasma capsulatum, lung infection and immunity. Future microbiology. 2015; [PubMed PMID: 26059620] |
[11] | Stockamp NW,Thompson GR 3rd, Coccidioidomycosis. Infectious disease clinics of North America. 2016 Mar; [PubMed PMID: 26739609] |
[12] | Gill CJ,Mwanakasale V,Fox MP,Chilengi R,Tembo M,Nsofwa M,Chalwe V,Mwananyanda L,Mukwamataba D,Malilwe B,Champo D,Macleod WB,Thea DM,Hamer DH, Impact of human immunodeficiency virus infection on Streptococcus pneumoniae colonization and seroepidemiology among Zambian women. The Journal of infectious diseases. 2008 Apr 1; [PubMed PMID: 18419536] |
[13] | Sorvillo F,Beall G,Turner PA,Beer VL,Kovacs AA,Kerndt PR, Incidence and determinants of Pseudomonas aeruginosa infection among persons with HIV: association with hospital exposure. American journal of infection control. 2001 Apr; [PubMed PMID: 11287873] |
[14] | Avino LJ,Naylor SM,Roecker AM, Pneumocystis jirovecii Pneumonia in the Non-HIV-Infected Population. The Annals of pharmacotherapy. 2016 Aug; [PubMed PMID: 27242349] |
[15] | Alcón A,Fàbregas N,Torres A, Pathophysiology of pneumonia. Clinics in chest medicine. 2005 Mar; [PubMed PMID: 15802164] |
[16] | Wu BG,Segal LN, The Lung Microbiome and Its Role in Pneumonia. Clinics in chest medicine. 2018 Dec; [PubMed PMID: 30390741] |
[17] | Freeman AM,Leigh, Jr TR, Viral Pneumonia 2020 Jan; [PubMed PMID: 30020658] |
[18] | Mayock RL,MacGregor RR, Diagnosis, prevention and early therapy of tuberculosis. Disease-a-month : DM. 1976 May; [PubMed PMID: 817877] |
[19] | Verver S,Bwire R,Borgdorff MW, Screening for pulmonary tuberculosis among immigrants: estimated effect on severity of disease and duration of infectiousness. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2001 May; [PubMed PMID: 11336272] |
[20] | Pneumonia in immunocompromised patients. Respirology (Carlton, Vic.). 2009 Nov; [PubMed PMID: 19857222] |
[21] | Rubin LG,Levin MJ,Ljungman P,Davies EG,Avery R,Tomblyn M,Bousvaros A,Dhanireddy S,Sung L,Keyserling H,Kang I, 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Feb; [PubMed PMID: 24311479] |
[22] | Kotton CN,Kumar D,Caliendo AM,Huprikar S,Chou S,Danziger-Isakov L,Humar A, The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun; [PubMed PMID: 29596116] |
[23] | Razonable RR,Humar A, Cytomegalovirus in solid organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013 Mar; [PubMed PMID: 23465003] |
[24] | Karakioulaki M,Stolz D, Biomarkers in Pneumonia-Beyond Procalcitonin. International journal of molecular sciences. 2019 Apr 24; [PubMed PMID: 31022834] |
[25] | Gonzalez C,Johnson T,Rolston K,Merriman K,Warneke C,Evans S, Predicting pneumonia mortality using CURB-65, PSI, and patient characteristics in patients presenting to the emergency department of a comprehensive cancer center. Cancer medicine. 2014 Aug; [PubMed PMID: 24802800] |
[26] | Ramirez JA,Wiemken TL,Peyrani P,Arnold FW,Kelley R,Mattingly WA,Nakamatsu R,Pena S,Guinn BE,Furmanek SP,Persaud AK,Raghuram A,Fernandez F,Beavin L,Bosson R,Fernandez-Botran R,Cavallazzi R,Bordon J,Valdivieso C,Schulte J,Carrico RM, Adults Hospitalized With Pneumonia in the United States: Incidence, Epidemiology, and Mortality. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 Nov 13; [PubMed PMID: 29020164] |
[27] | Fine MJ,Smith MA,Carson CA,Mutha SS,Sankey SS,Weissfeld LA,Kapoor WN, Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. JAMA. 1996 Jan 10; [PubMed PMID: 8531309] |
[28] | Mansharamani NG,Garland R,Delaney D,Koziel H, Management and outcome patterns for adult Pneumocystis carinii pneumonia, 1985 to 1995: comparison of HIV-associated cases to other immunocompromised states. Chest. 2000 Sep; [PubMed PMID: 10988192] |