Pneumonia in the Immunocompromised Host

Pneumonia is a common disease in children with both primary immunodeficiencies and secondary immunodeficiencies, such as cancer chemotherapy, transplantation, treatment of autoinflammatory diseases, human immunodeficiency virus, and malnutrition. Pneumonia and other infections of the respiratory tract have been identified by the Jeffrey Modell Foundation as one of the 10 warning signs of primary immunodeficiency. The broad array of pathogens and clinical presentations make pneumonia in this population a challenge. Understanding the organisms associated with specific immune defects helps inform appropriate empiric therapy, guide the diagnostic workup, identify patients with undiagnosed immunodeficiencies, choose the best treatment regimen for an immunocompromised patient, and prevent future infections. Additionally, new therapies, new patient populations, and new pathogens such as SARS-CoV-2 will create ongoing challenges to treating pneumonia in immunocompromised patients. Meeting the challenge to diagnose, treat, and prevent pneumonias in immunocompromised children will help decrease their attendant high morbidity and mortality.

Etiologic Agents And Epidemiology

The etiologic agents of pneumonia in the immunocompromised host include the same agents that cause community-acquired pneumonia (CAP) in immunocompetent hosts, plus healthcare-associated pneumonia (HAP) pathogens and opportunistic organisms. Some immune defects narrowly affect parts of the immune system, such as: neutrophil disorders (e.g., chronic granulomatous disease); antibody deficiency (e.g., X-linked agammaglobulinemia); CD4-lymphocyte defects (e.g., HIV); CD20-lymphocyte defects (e.g., rituximab therapy); or anti-TNF-α therapy. There is broader impact on patients with other immunodeficiencies, such as immediately post-hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT), severe combined immunodeficiency (SCID), or multiple immunosuppressive medications in patients with autoinflammatory diseases.

The arm of the immune system affected by the immunodeficiency governs vulnerability to certain opportunistic pathogens. Table 36.1 shows examples of immune defects and associated opportunistic pathogens associated with pneumonia. The position of SARS-CoV-2 on the list for vulnerability in primary or secondary immunodeficiency states awaits clarification.

TABLE 36.1

Microorganisms Associated With Pneumonia According to Immunodeficiency

Deficiency	Viruses	Bacteria (Except Mycobacteria)	Mycobacteria	Fungi
B-lymphocyte deficiency and antibody deficiency	Enteroviruses Adenoviruses Other respiratory viruses	Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Moraxella catarrhalis Pseudomonas spp. Neisseria meningitidis Mycoplasma spp.	None	None
T-lymphocyte deficiency (including tumor necrosis factor-α deficiency)	Varicella-zoster virus Herpes simplex virus Cytomegalovirus Adenovirus Respiratory syncytial virus Parainfluenza virus Human metapneumovirusRubeola virus	N. meningitidis Listeria monocytogenes Pseudomonas aeruginosa Stenotrophomonas maltophilia Burkholderia cepacia Legionella Nocardia Other opportunistic bacteria	Mycobacterium tuberculosis Mycobacterium avium complex Mycobacterium fortuitum Calmette-Guérin bacillus Other opportunistic mycobacteria	Pneumocystis jirovecii Candida spp. Histoplasma Cryptococcus
Neutrophil dysfunction (e.g., CGD)	None	S. aureus Burkholderia Serratia marcescens Nocardia	M. tuberculosis Calmette-Guérin bacillus Nontuberculous mycobacteria	Aspergillus spp. Candida spp.
Neutropenia (e.g., congenital and chemotherapy induced)	None	S. aureus Pseudomonas Stenotrophomonas Burkholderia Serratia Nocardia Other opportunistic bacteria	None	Aspergillus spp. Scedosporium apiospermum Candida spp. Mucormycetes

BAL, bronchoalveolar lavage; CBC, complete blood count; CGD, chronic granulomatous disease; CMV, cytomegalovirus; CT, computed tomography; DFA, direct fluorescent antigen staining; ETT, endotracheal tube; HSV, herpes simplex virus; LRTI, lower respiratory tract infection; PCR, polymerase chain reaction; PJP, Pneumocystis jirovecii pneumonia; VZV, varicella-zoster virus

Primary Immunodeficiency

Disorders of B Lymphocytes and Antibody Production

When the quantity or function of antibodies is deficient, such as in X-linked agammaglobulinemia or common variable immunodeficiency (CVID), recurrent bacterial pneumonia is a hallmark of the disease. In a systematic review, between 37%–90% of patients with primary antibody deficiencies initially presented with pneumonia. In this population, pneumonia largely is caused by organisms that normally colonize the respiratory tract including Streptococcus pneumoniae, various species of Haemophilus , other encapsulated bacteria, and atypical bacteria including Mycoplasma species. Pneumonia due to respiratory viruses is not more frequent or more severe in antibody deficiency states.

Disorders of T Lymphocytes

In conditions of cell-mediated immunodeficiency, such as severe combined immunodeficiency (SCID) or 22q11 deletion (DiGeorge syndrome), pneumonia typically is caused by opportunistic and viral pathogens. These viruses include the human herpesviruses, especially cytomegalovirus, varicella-zoster virus (VZV), herpes simplex virus (HSV), and, occasionally, human herpesvirus 6 (HHV-6), all of which are unusual causes of clinically significant pneumonia in healthy children. Common respiratory viruses, particularly respiratory syncytial virus (RSV), parainfluenza viruses, human metapneumovirus, and adenovirus, can cause prolonged, severe, life-threatening infections. Lymphocyte deficiencies also predispose to pneumonia due to many bacteria (see Table 36.1 ), as well as several fungi, including Pneumocystis jirovecii .

Disorders of Phagocytes

In patients with impaired phagocyte function, including those with chronic granulomatous disease (CGD), pneumonia occurs commonly. In several large case-series from the US and Europe, pneumonia had occurred in 66%–87% of people living with CGD. Pneumonia is frequently caused by Staphylococcus aureus (including methicillin-resistant strains, MRSA) and opportunistic bacteria and fungi such as Pseudomonas aeruginosa , Burkholderia cepacia , Nocardia spp., Mycobacterium tuberculosis (particularly in areas where it is endemic), nontuberculous mycobacteria, and Aspergillus spp. ^, Patients with leukocyte adhesion deficiency (LAD) have recurrent serious bacterial infections including pneumonia. Phagocyte disorders alone do not appear to predispose to either viral or Pneumocystis jirovecii pneumonia (PCP).

Disorders of Complement

Patients with complement deficiency are at increased risk of recurrent pneumonia due to encapsulated bacteria such as S. pneumoniae , H. influenzae , and occasionally S. aureus .

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