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CME: Immunology

Infectious disease considerations in immunocompromised patients

McGrath, Bridget MPAS, PA-C; Broadhurst, Mary MPAS, PA-C; Roman, Christopher MMS, PA-C

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Journal of the American Academy of Physician Assistants: September 2020 - Volume 33 - Issue 9 - p 16-25
doi: 10.1097/01.JAA.0000694948.01963.f4
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Box 1
Box 1

The number of immunosuppressed patients in the United States has risen in recent decades. The 2013 National Health Interview Survey estimated that 2.7% of the population was immunocompromised.1 Immunosuppression can arise from a variety of causes, including specific diseases or drugs that improve and/or extend life.

Depending on the nature of their immunosuppression, patients may be at risk for a variety of infectious complications, both common and rare. Immunosuppressed patients may not have typical symptoms of infection, which can delay care and present a diagnostic challenge. This article summarizes five common causes of immunosuppression: asplenia, HIV infection, solid organ transplant, biologic medications for autoimmune diseases (such as inflammatory bowel disease and psoriasis), and cancer (tumor- and treatment-related). Each of these causes will be discussed with regard to the pathophysiology of immunosuppression, infectious risks and other considerations, appropriate prophylaxis and/or treatment, and vaccinations.

Box 2
Box 2


This heterogeneous group comprises patients with surgical asplenia, functional hyposplenism, and (rarely) congenital asplenia. Numerous diseases may be associated with functional hyposplenia, including sickle cell disease, celiac disease, autoimmune diseases, liver cirrhosis, and graft versus host disease.2 As of 2014, about 25,000 surgical splenectomies were performed annually in the United States, and the total number of patients with asplenia was estimated at 1 million, including 70,000 to 100,000 persons with sickle cell disease.3


The spleen serves multiple important roles in immune system function, contributing to complex adaptive immune responses and clearing pathogens from the blood.4 The spleen also plays an important role in the production and maturation of B-memory lymphocytes and other substances such as opsonins. These are crucial for fighting infections, specifically those caused by encapsulated organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B.5 Because patients with asplenia lack these defensive substances, they are at risk for episodes of rapidly progressive septicemia.

Infectious risks and other considerations

Overwhelming postsplenectomy infection (OPSI) refers to the development of fulminant sepsis in patients with asplenia, often due to encapsulated organisms causing meningitis or pneumonia.6 A patient with OPSI can present with mild symptoms of infection, such as mild flu-like illness, and rapidly progress to fulminant sepsis and death.6 Although relatively rare, OPSI is a medical emergency with a mortality of 50% to 70% if treatment is delayed or inadequate.6


Patients with asplenia who have fever or other signs and symptoms of infection should be treated promptly with broad-spectrum antibiotics and observed for up to 72 hours, pending culture results. Empiric treatment can include ceftriaxone with vancomycin. Ceftriaxone targets the three most important bacterial considerations for these patients: S. pneumoniae strains, H. influenzae, and N. meningitides.3 Additionally, ceftriaxone has coverage for many community-acquired Gram-negative bacilli, including Capnocytophaga, a pathogen often linked to animal bites.3,6

Prophylactic antimicrobial therapy often is recommended for children with asplenia who are under age 5 years, for 1 to 2 years following a splenectomy.3 Lifetime antimicrobial prophylaxis can be considered for patients who have had an episode of OPSI.3

Clinicians should regularly review specific immunization guidelines for these patients. Coverage for encapsulated organisms and influenza virus is routinely recommended (Table 1).7 Recommendations for timing of the initial vaccination series reflect the cause of asplenia: at least 14 days postoperatively for patients undergoing emergency splenectomy, 8 to 10 weeks (but no later than 14 days) before routine splenectomy, and as soon as the impairment is identified for patients with functional asplenia.2,8

CDC-recommended vaccination schedule for patients over age 19 years who are considered asplenic7


An estimated 1.2 million people in the United States are living with HIV; about 162,500 (14.5%) of them have not been diagnosed.9,10 Improvements in antiretroviral therapy have gradually made HIV a chronic disease requiring decades of therapy, with life expectancy approximating that of the general population.11 Despite these improvements, a subpopulation of patients with HIV may still develop significant immunosuppression through lack of diagnosis, failure to adhere to a treatment regimen, or by developing resistance to antiretroviral therapy.


HIV infection affects several components of the immune system, including B-lymphocytes, T-lymphocytes (CD4 and CD8), and lymphoid tissue; however, the immunosuppression that occurs with HIV is tied most closely to the abundance and function of CD4 T-lymphocytes.12 CD4 cells govern a variety of immunologic activities, including inducing B lymphocytes to produce antibodies, activating macrophages, recruiting granulocytes, and producing cytokines.13 In healthy patients, CD4 cell counts vary widely, with 500 cells/mm3 as the lower limit of normal.14 HIV causes a decline in the number of CD4 cells due to cell death as well as altered cellular production, differentiation, and regulation. The CD4 lymphocytes that remain are dysfunctional, with changes in cytokine production and other deviations from normal activity.15 HIV transitions to AIDS when CD4 count drops below 200 cells/mm3, or an HIV-infected patient develops an AIDS-defining condition or opportunistic infection (Table 2) irrespective of CD4 count.16,17

Opportunistic infections based on patient CD4 count

Infectious risks and other considerations

Infections are the most common cause of fever in patients with HIV, but malignancies (predominantly lymphoma) are another important cause.18-20 Clinicians must be aware that AIDS-defining conditions can be noninfectious, such as lymphoma, generalized lymphadenopathy, wasting syndrome, and a variety of symptoms affecting virtually every organ system.21

Carefully evaluate patients with HIV who present with fever. Obtain a complete history and physical examination and integrate it with diagnostic testing. Give specific consideration to the patient's most recent CD4 count.

Patients with HIV and normal CD4 counts (greater than 500 cells/mm3) often manifest with the same types of infections as the general population. An important exception is mycobacterial infections. Multiple studies have found that tuberculosis (TB) and atypical mycobacterial pathogens cause about half of fevers in patients with HIV.18-20

Pneumocystis jirovecii is a common cause of opportunistic infections not only in patients with HIV, but also in many other immunocompromised patients, including those with solid organ or stem cell transplants, hematologic malignancies, and those taking biologic agents or other immunosuppressants. Patients with HIV or AIDS often develop symptoms of a P. jirovecii infection over the course of weeks; HIV-negative immunocompromised patients often develop symptoms over the course of days, usually presenting with only a high fever.22 Pulmonary disease is the most common presentation of P. jirovecii in patients with HIV or AIDS. Patients typically manifest with subacute symptoms of worsening nonproductive cough and hypoxia. Classic chest radiograph findings of P. jirovecii pneumonia include bilateral perihilar interstitial infiltrates that become progressively homogenous and diffuse on serial imaging.23 CT scan imaging historically displays extensive ground-glass infiltrates, but this can be seen with other disorders, such as interstitial lung disease and COVID-19.23 Induced sputum or bronchoalveolar lavage will facilitate confirmatory testing.

Although cultures may not be necessary in all cases (for example, a straightforward infection in a patient with a high CD4 count), clinicians should have a low threshold for ordering blood or other cultures, including typical pathogens as well as fungal organisms and mycobacteria. Patients with low CD4 counts should be aggressively tested for opportunistic infections. Fungal and mycobacterial cultures can take weeks to yield a final result, and some fungi are difficult to culture. Additional fungal testing with serologies, complement fixation, or direct antigen testing may be needed, depending on regionally endemic infections and clinical suspicion. Consulting with infectious disease and other specialists is an important aspect of managing these complicated patients.


Opportunistic infections and noninfectious complications of HIV are extensively discussed in other publications, and a comprehensive overview is beyond the scope of this article (Table 3).24 Vaccination of patients with HIV conforms to the 2019 adult immunization schedule published by the Advisory Committee on Immunization Practices with the exception of live vaccines. Live vaccines (live-attenuated influenza virus, measles-mumps-rubella, varicella/zoster) are contraindicated in patients with HIV and CD4 counts below 200.25

Updates to the guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV24


The year 2019 was the seventh consecutive record-breaking year for organ transplants in the United States, up nearly 9% from 2018.26 Recipients are prescribed an array of immunosuppressive medications to prevent rejection of a donated organ.


If the patient's immune system is unchecked, it can lead to organ damage and/or rejection. Potent immunosuppressants including glucocorticoids, calcineurin inhibitors, mTOR inhibitors, and antimetabolite drugs dramatically reduce the chance of rejection of transplanted solid organs (Table 4).27,28 However, because of their altered immune systems, transplant recipients are at increased risk for infection, compared with the general population.

Immunosuppressive role of post-transplantation medications27,28

Infectious risks and other considerations

The risk of post-transplant infection is predominantly determined by two factors: epidemiologic exposures and the degree of immunosuppression, both of which vary over time.28,29 Therefore, when a transplant recipient presents with infection, clinicians must consider timing since transplantation, recipient/donor exposures, and current degree of immunosuppression.28

Bacterial and fungal infections are most common within the early post-transplant period (the first 30 days after surgery).30 Infections during this time usually are donor-derived, recipient-derived, or due to surgical complications.28,30 During the late transplant period (6 months or more after surgery), immunosuppressive therapy is tailored and lowers the transplant recipient's overall risk of infection. However, because of their need for lifelong immunosuppression, these patients remain at an increased risk for community-acquired infections.28

Invasive fungal infections are common in transplant recipients, with Candidiasis, Cryptococcosis, and molds such as Aspergillus and Zygomycosis most commonly reported.31 Endemic fungi and regional species such as Histoplasma, Coccidioides and Blastomyces also are important causative agents.31

Viral illnesses and allograft rejection are the most common causes of fever in the intermediate post-transplant period (1 to 6 months).29,30

BKvirusinfection typically occurs in childhood, with 50% of children undergoing seroconversion by age 4 years.32 Reactivation of latent infection often occurs after renal transplantation. Up to 10% of renal transplant patients develop BK virus nephropathy, which can result in graft loss.33 Common complications include BK virus-associated nephropathy, ureteral stenosis, and hemorrhagic cystitis.

Cytomegalovirus(CMV) remains one of the most common complications affecting patients who have had organ transplants.34,35 About 50% of the US population is seropositive for CMV and most patients experience an asymptomatic or mild primary infection, followed by latent infection.36 Following transplantation, patients may develop viremia without focal signs or symptoms, or localized CMV disease. CMV disease correlates with the presence of detectable CMV in clinical specimens accompanied by other clinical manifestations or invasive disease, which may lead to end-organ damage.35 CMV disease, confirmed via quantitative serum testing, often presents with a syndrome of fever, malaise, leukopenia, and/or thrombocytopenia; many organ systems can be affected by this virus.34,35 Common sites for an active CMV infection include the eyes, gastrointestinal (GI) tract, liver, lungs, and central nervous system. CMV can lead to an array of complications such as acute or chronic allograft rejection, and organ-specific complications such as bronchiolitis obliterans in lung transplant recipients or tubulointerstitial fibrosis in kidney transplant recipients.35 CMV disease increases transplant recipient mortality, specifically in patients who have received lungs or small intestines.35

Epstein-Barr virus(EBV) primary infection and subsequent dormant disease affects up to 90% of adults.37 EBV can be reactivated to cause a wide spectrum of disease, ranging from asymptomatic viremia to infectious mononucleosis syndrome. The latter is characterized by fever, exudative tonsillitis, cervical lymphadenopathy (particularly in the posterior chain), and splenomegaly. Atypical lymphocytosis is common, but is not specific for EBV infection. EBV also is associated with the development of certain malignancies, such as post-transplant lymphoproliferative disorder and Burkitt lymphoma.

Other viruses that can remain dormant in patients but cause disease post-transplant include varicella zoster and herpes simplex.29 Maintain a low threshold for testing suspicious skin lesions for these viruses in transplant recipients.


Prophylaxis and infectious treatment management are unique to each solid organ recipient, based on donor and recipient exposure, organ transplanted, and time since transplantation. Primary care providers should be familiar with the following:

Opportunistic infections. Post-transplant patients should be on low-dose trimethoprim-sulfamethoxazole (one single-strength tablet once daily or one double-strength three times weekly, with consideration for renal function) or alternative prophylactic therapy such as atovaquone or dapsone. The primary goals of prophylaxis are prevention of P. jirovecii pneumonia as well as other opportunistic and common urinary, respiratory, and GI bacterial infections.

BK virus. Although no specific antiviral treatment exists for BK virus, treatment consists of reducing immunosuppression with institution-dependent addition of IV immunoglobulin or other antivirals such as leflunomide or cidofovir.

CMV. Donors and recipients are screened for CMV before organ transplantation. CMV-negative transplant recipients whose donors are CMV-positive are at the greatest risk of developing CMV disease.28 CMV prophylaxis often is started 10 days post-transplant and continued for at least 3 to 6 months.34 Valganciclovir is the most commonly used drug for prophylaxis; acyclovir, valacyclovir, and ganciclovir also are used.34 In case of infection, the recommended first-line treatments for CMV infection are valganciclovir or ganciclovir.34

EBV. Low levels of EBV viremia can be monitored with serial blood tests. Consult transplant specialists if the patient's levels continue to rise, as immunosuppression often is reduced in these patients to prevent further EBV replication.

In the case of post-transplant lymphoproliferative disorder (PTLD), resection or radiotherapy can be considered for localized disease. For systemic therapy, rituximab, a monoclonal antibody directed against CD20, and other chemotherapy agents often are used.37

The pneumococcal vaccine series is recommended for solid-organ recipients, starting with a single dose of pneumococcal conjugate vaccine (PCV 13) followed by a dose of the pneumococcal polysaccharide vaccine (PPSV23) for patients older than age 19 years.7 Revaccination with PPSV23 should take place every 3 to 5 years.29 Influenza vaccination is recommended annually.29 Live vaccines (varicella, measles, mumps, rubella, live-attenuated influenza vaccination) generally are contraindicated after transplantation because they may cause disseminated disease in immunocompromised patients.29


Autoimmune diseases such as rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease, and multiple sclerosis affect an estimated 4.5% of the Western world.38 Conventional therapy includes disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids, but advances in drug development have led to new therapeutic options: genetically manufactured molecules from living cells, including monoclonal antibodies. These biologic agents target specific parts of the immune system and are approved for use in several immune-mediated inflammatory diseases, as well as a few lymphoproliferative disorders.


Immune-mediated inflammatory diseases are associated with overproduction of different cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and the interleukins IL-1, IL-6, and IL-23).39 These molecules have important immunologic functions, including activating macrophages, recruiting neutrophils, maintaining granulomas, stimulating immune cells, producing proinflammatory mediators, and forming immunoglobulins and inflammatory cytokines. Through these mechanisms, immune-mediated diseases cause hyperactivity of immune cells, such as T helper and B cells. Biologic agents target these molecules and cells to modulate disease. However, as a result, normal immune functions are suppressed, increasing the patient's risk for infection.40

The most commonly used biologics are anti-TNF-alpha agents such as etanercept, infliximab, adalimumab, certolizumab, and golimumab. Less-commonly used agents include anti-CD20/B cell agents (rituximab), T-cell costimulation modulators (abatacept), and anti-interleukin agents (anakinra, ustekinumab, and tocilizumab).

Infectious risks and other considerations

All biologics are associated with an increased risk of bacterial, fungal, and viral infections, particularly anti-TNF-alpha agents, which have been the most well-studied to date.41 In addition to an increased rate of routine community-acquired bacterial infections, invasive skin and soft-tissue infections, and septic arthritis, patients taking biologics are at risk for other opportunistic or reactivated infections (Table 5).42-52 As with other immunocompromised patients, these patients may present with atypical or nonspecific symptoms. If a patient is suspected of having an invasive infection, maintain a low threshold for inpatient admission and consider routine and esoteric infections.

Specific infectious considerations in immunosuppressed hosts receiving biologics44-52


According to the most recent recommendations, before starting any biologic agent, patients should be screened and treated for TB as well as hepatitis B and C.53 Screening for TB includes either the tuberculin skin test or interferon-gamma release assay. If either test is negative, no further workup is needed and the patient may start the biologic; if positive, a chest radiograph and sputum acid-fast bacillus stain/cultures should be obtained, and the biologic withheld. Latent TB is diagnosed with either a normal or abnormal chest radiograph (for example, cavitation, fibrosis, or scarring usually in apical regions) and negative sputum acid-fast bacillus stain/cultures. Active TB is diagnosed with an abnormal chest radiograph and positive sputum acid-fast bacillus stain/cultures. Patients with either active or latent TB should start treatment immediately. In patients with latent TB, oral rifampin (10 mg/kg daily; maximum 600 mg) for 4 months is recommended; a biologic agent may be started after 1 month of treatment.53,54 Patients with active TB should be prescribed the following oral regimen for 2 months: rifampin (10 mg/kg daily; maximum 600 mg), isoniazid (5 mg/kg daily; maximum 300 mg), pyrazinamide (1,000 to 2,000 mg daily depending on body weight), and ethambutol (800 to 1,600 mg daily depending on body weight).55 The rifampin and isoniazid dosages should be continued for an additional 4 to 7 months, and the patient must wait to start the biologic until after this treatment is complete.53

In patients with chronic hepatitis B (positive HBsAg), antiviral therapy (entecavir or tenofovir) should be given concurrently with biologics. Close monitoring of liver enzymes and viral load is paramount. Patients with resolved hepatitis B (negative HBsAg and positive HBcAb) are at risk for viral reactivation and require viral load monitoring every 1 to 3 months.56 Any patient who tests positive for hepatitis C should be treated with antivirals such as glecaprevir-pibrentasvir.57 Optimal treatment with biologics in patients with hepatitis C is not known; however, conditional recommendations suggest concurrent therapy with an antiviral and collaboration with a hepatologist and/or gastroenterologist.53 Screening for non-TB mycobacterium and other fungal infections (such as histoplasmosis, coccidioidomycosis, and aspergillosis) is not recommended; testing should be pursued if there is clinical suspicion for infection.

In addition to screening, vaccinations—including varicella, pneumococcal, and influenza—should be updated. Live vaccinations should not be given while patients are on biologic therapy; rather, these live vaccines may be given 1 month before starting therapy or 1 month after discontinuing it. Antimicrobial prophylaxis is not routinely recommended; however, Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole can be considered in high-risk patients on concurrent biologic therapy and corticosteroids (that is, patients receiving more than 20 mg of prednisone daily for more than 1 month).58

Treatment of infections in patients on biologics tends to be aggressive because of the risk of severe and disseminated disease. Despite this necessary consideration, treatment guidelines are not present in the literature due to two complex factors. First, patients on biologic therapy often are at an increased risk for infection at baseline because of their specific underlying immune-mediated disease. Second, biologics can alter specific immunologic targets, leading to a multitude of unique infectious risks. These intertwined, complex factors must be considered by primary care providers when developing an infectious differential in patients taking biologics for immune-mediated inflammatory diseases.59 Management should include prompt discussion with the prescribing clinician about dose reduction or cessation, as well as referral to an infectious disease specialist.


Cancer remains a significant health burden in the United States, claiming more than 600,000 lives annually, second only to heart disease as a leading cause of death.60,61 Nearly 16 million people in the United States have cancer (excluding nonmelanoma skin cancers and carcinoma in situ), with an estimated 1.8 million new cancer diagnoses expected in 2020.60 Most of these new cases are solid tumors, with cancers of the breast, lung and bronchus, prostate, and colon and rectum being the most common. Hematologic malignancies, including leukemia, lymphoma, and myeloma, account for about 10%.60 Infection is an important complication of every type of cancer, leading to costly hospital admissions (particularly for neutropenic fever) and high mortality.62,63


Several factors related to a malignancy itself or its treatment can increase patients' risk for infection.

Tumor-related factors. Immunosuppression caused by bone marrow infiltration occurs in hematologic malignancies in which the primary cancer cells originate in the marrow, alter blood cell lines, and thereby disrupt the normal immune response. This also can occur with nonhematologic cancers when metastases travel to the bone marrow. Solid tumors seldomly cause immunosuppression directly. Instead, these types of cancers increase the risk of infection by other methods, such as obstruction of anatomic passageways, alteration of defense mechanisms, and disruption of natural barriers in their respective locations.64 These changes in turn may lead to local or systemic inflammation and infection.

Treatment-related factors. Chemotherapy agents target rapidly dividing cells with the goal of killing cancer cells. Unfortunately, these agents often are not cancer-specific, and may destroy rapidly dividing healthy cells, which are abundant in the hair, skin, GI tract, and bone marrow. Damage to the skin and GI tract lets pathogens breach innate immune barriers, leading to increased risk of infection. In the bone marrow, chemotherapy destroys immune cells, causing myelosuppression and immunosuppression. Although the degree of immunosuppression varies based on the chemotherapy agents used, cytotoxic antineoplastic regimens that target the bone marrow—and are used to treat leukemias and other hematologic cancers—tend to cause greater immunosuppression that can be profound and persistent. All cell lines are affected, including neutrophils, which are important mediators in the initial immune response to bacterial and fungal infections. When absolute neutrophil count falls below 1,000 cells/mcL (normal values range between 1,500 and 8,000 cells/mcL), patients are considered neutropenic. In these patients, infection risk is inversely related to the absolute neutrophil count, and the risk of invasive infections increases substantially when that level falls below 500 cells/mcL.65 Generally, patients at high risk for infection are defined as those with prolonged and profound neutropenia (less than 100 cells/mcL for more than 7 days). Low-risk patients are those with neutropenia lasting less than 7 days.66

Infectious risks and other considerations

Tumor-related. Obstruction of anatomic passageways and disruption of tissues can lead to local or systemic infection. Infections vary based on the primary tumor site, such as the lung (postobstructive pneumonia), biliary tree (ascending cholangitis), or urinary tract (pyelonephritis). These infections can be further complicated by abscess or fistula formation, as well as bacteremia. Often, the pathogens isolated from such sites are normal anatomic flora.67

Treatment-related. Fever is common in patients with chemotherapy-induced neutropenia. Often, no cause can be identified; only 20% to 30% of patients with febrile episodes have a documented infection.68 Bacteremia may be the only evidence of infection, occurring in 10% to 25% of patients with neutropenic fever.68 Recently, an epidemiologic shift has occurred, with Gram-positive organisms such as Staphylococcus sp. now being more common than Gram-negative infections such as Pseudomonas aeruginosa.69 Community-acquired respiratory viral infections as well as reactivated viral infections such as herpes simplex and varicella zoster are common in high-risk patients with prolonged neutropenia and/or those taking long-term high-dose corticosteroids.70-72 Invasive fungal infections, such as those caused by Candida sp. and Aspergillus sp., also are more common in high-risk patients with neutropenia and should be considered in patients with persistent fevers after the first week of neutropenia.68

In patients receiving targeted cancer therapy, the risk for opportunistic infection depends on the medication. For example, the anti-CD52 monoclonal antibody alemtuzumab carries a significant risk for CMV reactivation, as well as potential for developing Pneumocystis pneumonia, aspergillosis, and other invasive fungal infections.73,74 The PI3K inhibitor idelalisib is associated with an increased risk of Pneumocystis pneumonia and CMV.75 Increasing evidence associates the Bruton tyrosine kinase (BTK) inhibitor ibrutinib with the threat of opportunistic infections such as Pneumocystis pneumonia and invasive fungal infections such as pulmonary cryptococcosis and aspergillosis.76 Herpes simplex and varicella zoster reactivation also are associated with these medications, as well as with high-dose corticosteroids.


Tumor-related. Antimicrobial prophylaxis is not routinely recommended for patients with solid tumors.66 Reducing disease burden by way of tumor resection, chemotherapy, radiation, or a combination of these modalities is the treatment of choice for obstruction. Other options, depending on tumor location, include stent placement, percutaneous drainage, or laser therapy. Antibiotics are used alone or in conjunction with these therapies to treat secondary infection.

Chemotherapy-related. The American Society of Clinical Oncology and Infectious Disease Society of America published specific guidelines addressing the prophylactic management of patients with cancer treatment-related immunosuppression and the treatment of neutropenic syndromes.66,68 Both guidelines stress the importance of initial risk assessment in patients with neutropenia, categorizing them into the aforementioned high-risk population (absolute neutrophil count less than 100 cells/mcL for more than 7 days) and low-risk (absolute neutrophil count less than 500 cells/mcL for less than 7 days). Early consultation with an infectious-disease specialist is emphasized. Concurrent prophylaxis with antibiotic (fluoroquinolone), antifungal (azole or echinocandin), and antiviral (nucleoside analogue) agents is recommended for high-risk patients during the neutropenic period. Additionally, patients who are at more than a 3.5% risk for P. jirovecii pneumonia (defined as receiving more than 20 mg prednisone daily for more than 30 days or those receiving purine analogues) also should receive appropriate prophylaxis.66

Although fever often is the only sign of infection, clinicians should be cognizant that severely neutropenic patients can sometimes present in an afebrile or hypothermic state.66 Evaluation of patients presenting with fever or suspected infection includes two sets of blood cultures, chest radiographs, and urinalysis with urine culture if indicated. Additional studies and cultures from suspected sites of infection also may be warranted.68 Treatment of high-risk patients who are febrile and neutropenic includes expeditious IV antipseudomonal antibiotics (such as cefepime) until 48 hours of negative cultures. Empiric Gram-positive coverage is not indicated (even in patients with an indwelling venous catheter), but should be considered in patients presenting with severe sepsis, pneumonia, suspected catheter-related infection, Gram-positive bacteremia, skin or soft-tissue infection, severe mucositis, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, or penicillin-resistant Pneumococcus colonization. Empiric antifungal agents with antimold activity (such as voriconazole, echinocandin, or amphotericin B) also are recommended for patients with hemodynamic instability, persistent fevers without clear source, or expected neutropenia of more than 7 days.68 Adjustments to antimicrobials should be guided by clinical and microbiologic data, and documented infections treated for the appropriate duration. De-escalation to oral antibiotics in stable patients with neutropenia is recommended after the primary infection is treated and until bone marrow recovery (absolute neutrophil count greater than 500 cells/mcL).68

In patients receiving targeted cancer therapy, recommendations for antimicrobial prophylaxis (including for Pneumocystis) depend on the medication regimen. In patients who are at high risk for CMV reactivation (that is, those taking alemtuzumab or idelalisib), weekly laboratory monitoring for CMV is recommended.73,77 At this time, no formal recommendations exist for routine antimicrobial prophylaxis in patients receiving oral BTK inhibitors.

Vaccinations are an important preventive measure in patients with solid tumors and those with hematologic malignancies. Influenza and pneumococcal (PCV13 followed by PPSV23) vaccines are recommended for all patients with cancer, except those receiving anti-B-cell antibodies (such as rituximab) and intensive chemotherapy (such as induction or consolidation therapy for leukemia).78 Other vaccinations should be updated as needed.

Timing of vaccination is important, particularly in patients receiving chemotherapy. When possible, all indicated vaccinations should be given before chemotherapy (at least 2 weeks before for inactive vaccines and at least 4 weeks before for live vaccines). Do not administer inactive and live vaccinations during chemotherapy (with the exception of the influenza vaccine). Inactive and live vaccines may be given 3 months after completion of chemotherapy; in patients who received anti-B-cell antibodies, this period is extended to 6 months.78


Primary care providers are likely to be the first point of contact for immunocompromised patients experiencing infectious complications. These patients are vulnerable to uncommon pathogens and often have atypical symptoms. As a result, clinicians should have a lower threshold for expanded diagnostic testing as well as for referral and/or hospitalization when caring for these patients. Coordination with infectious disease and other specialties is another integral part of the ongoing management of immunocompromised patients.

Complications arising from infection are common in these patients and can present a diagnostic and therapeutic challenge. Appropriate prophylaxis, treatment, and vaccinations—including prompt evaluation and action—can help slow or prevent the progression of infectious complications, leading to more favorable patient outcomes.


1. Harpaz R, Dahl RM, Dooling KL. Prevalence of immunosuppression among US adults, 2013. JAMA. 2016;316(23):2547–2548.
2. Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet. 2011;378(9785):86–97.
3. Rubin LG, Schaffner W. Clinical practice. Care of the asplenic patient. N Engl J Med. 2014;371(4):349–356.
4. Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol. 2005;5(8):606–616.
5. Kirkineska L, Perifanis V, Vasiliadis T. Functional hyposplenism. Hippokratia. 2014;18(1):7–11.
6. Sinwar PD. Overwhelming post splenectomy infection syndrome—review study. Int J Surg. 2014;12(12):1314–1316.
7. Centers for Disease Control and Prevention. Recommended adult immunization schedule for ages 19 or older. Accessed June 8, 2020.
8. Harji DP, Jaunoo SS, Mistry P, Nesargikar PN. Immunoprophylaxis in asplenic patients. Int J Surg. 2009;7(5):421–423.
9. Centers for Disease Control and Prevention. Diagnoses of HIV infection in the United States and dependent areas, 2016. HIV Surveillance Report. 2017. Accessed June 8, 2020.
10. Centers for Disease Control and Prevention. Estimated HIV incidence and prevalence in the United States, 2010-2015. HIV Surveillance Supplemental Report. 2018;23(1).
11. Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One. 2013;8(12):e81355.
12. Young J, Psichogiou M, Meyer L, et al. Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. CD4 cell count and the risk of AIDS or death in HIV-infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE. PLoS Med. 2012;9(3):e1001194.
13. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557–1569.
14. Maini MK, Gilson RJ, Chavda N, et al. Reference ranges and sources of variability of CD4 counts in HIV-seronegative women and men. Genitourin Med. 1996;72:27–31.
15. Douek DC, Roederer M, Koup RA. Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med. 2009;60:471–484.
16. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41(RR-17):1–19.
18. Miller RF, Hingorami AD, Foley NM. Pyrexia of undetermined origin in patients with human immunodeficiency virus infection and AIDS. Int J STD AIDS. 1996;7(3):170–175.
19. Sullivan M, Feinberg J, Bartlett JG. Fever in patients with HIV infection. Infect Dis Clin North Am. 1996;10(1):149–165.
20. Bissuel F, Leport C, Perronne C, et al. Fever of unknown origin in HIV-infected patients: a critical analysis of a retrospective series of 57 cases. J Intern Med. 1994;236(5):529–535.
21. Selik RM, Mokotoff ED, Branson B, et al. Revised surveillance case definition for HIV infection—United States, 2014. MMWR Recomm Rep. 2014;63(RR03):1–10.
22. Kovacs JA, Hiemenz JW, Macher AM, et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med. 1984;100(5):663–671.
23. Thomas CF Jr, Limper AH. Pneumocystis pneumonia. N Engl J Med. 2004;350(24):2487–2498.
24. Centers for Disease Control and Prevention, National Institute of Health, HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Accessed June 2, 2020.
25. Kim DK, Hunter P; on behalf of the Advisory Committee on Immunization Practices. Recommended adult immunization schedule, United States, 2019. Ann Intern Med. 2019;170(3):182–192.
26. OPTN. Organ donation again sets record in 2019. Accessed June 2, 2020.
27. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351(26):2715–2729.
28. Fishman JA, Issa NC. Infection in organ transplantation: risk factors and evolving patterns of infection. Infect Dis Clin North Am. 2010;24(2):273–283.
29. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357(25):2601–2614.
30. Green M. Introduction: infections in solid organ transplantation. Am J Transplant. 2013;13(suppl 4):3–8
31. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101–1111.
32. Pinto M, Dobson S. BK and JC virus: a review. J Infect. 2014;68(suppl 1):S2–S8.
33. Jamboti JS. BK virus nephropathy in renal transplant recipients. Nephrology (Carlton). 2016;21(8):647–654.
34. Kotton CN, Kumar D, Caliendo AM, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2018;102(6):900–931.
35. Razonable RR, Humar A. Cytomegalovirus in solid organ transplantation. Am J Transplant. 2013;13(suppl 4):93–106.
36. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010;50(11):1439–1447.
37. Dunmire SK, Verghese PS, Balfour HH Jr. Primary Epstein-Barr virus infection. J Clin Virol. 2018;102:84–92.
38. Hayter SM, Cook MC. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun Rev. 2012;11(10):754–765.
39. Moudgil KD, Choubey D. Cytokines in autoimmunity: role in induction, regulation, and treatment. J Interferon Cytokine Res. 2011;31(10):695–703.
40. Koo S, Marty FM, Baden LR. Infectious complications associated with immunomodulating biologic agents. Infect Dis Clin North Am. 2010;24(2):285–306.
41. Galloway JB, Hyrich KL, Mercer LK, et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford). 2011;50(1):124–131.
42. Dixon WG, Watson K, Lunt M, et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2006;54(8):2368–2376.
43. Galloway JB, Hyrich KL, Mercer LK, et al. Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011;70(10):1810–1814.
44. Tubach F, Ravaud P, Salmon-Céron D, et al. Emergence of Legionella pneumophila pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis. 2006;43(10):e95–e100.
45. Slifman NR, Gershon SK, Lee J-H, et al. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum. 2003;48(2):319–324.
46. Dixon WG, Hyrich KL, Watson KD, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2010;69(3):522–528.
47. Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumour necrosis factor therapy in USA. Ann Rheum Dis. 2013;72(1):37–42.
48. Galloway JB, Mercer LK, Moseley A, et al. Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2013;72(2):229–234.
49. Vassilopoulos D, Calabrese LH. Viral hepatitis: review of arthritic complications and therapy for arthritis in the presence of active HBV/HCV. Curr Rheumatol Rep. 2013;15(4):319.
50. Hage CA, Bowyer S, Tarvin SE, et al. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis. 2010;50(1):85–92.
51. Taroumian S, Knowles SL, Lisse JR, et al. Management of Coccidioidomycosis in patients receiving biologic response modifiers or disease-modifying antirheumatic drugs. Arthritis Care Res (Hoboken). 2012;64(12):1903–1909.
    52. Tsiodras S, Samonis G, Boumpas DT, Kontoyiannis DP. Fungal infections complicating tumor necrosis factor alpha blockade therapy. Mayo Clin Proc. 2008;83(2):181–194.
    53. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1–26.
    54. Sterling TR, Njie G, Zenner D, et al. Guidelines for the treatment of latent tuberculosis infection: recommendations from the national tuberculosis controllers association and CDC, 2020. MMWR Recomm Rep. 2020;69(1):1–11.
    55. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63(7):e147–e195.
    56. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–1599.
    57. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed June 7, 2020.
    58. Rodriguez M, Fishman JA. Prevention of infection due to Pneumocystis Spp. in human immunodeficiency virus-negative immunocompromised patients. Clin Microbiol Rev. 2004;17(4):770–782.
    59. Koo S, Marty FM, Baden LR. Infectious complications associated with immunomodulating biologic agents. Infect Dis Clin North Am. 2010;24(2):285–306.
    60. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2017. Bethesda, MD: National Cancer Institute. Accessed June 7, 2020.
    61. Heron M. Deaths: leading causes for 2017. Natl Vital Stat Rep. 2019;68(6):1–77.
    62. Tai E, Guy GP, Dunbar A, Richardson LC. Cost of cancer-related neutropenia or fever hospitalizations, United States, 2012. J Oncol Pract. 2017;13(6):e552–e561.
    63. Lyman GH, Michels SL, Reynolds MW, et al. Risk of mortality in patients with cancer who experience febrile neutropenia. Cancer. 2010;116(23):5555–5563.
    64. Rolston KVI. Infections in cancer patients with solid tumors: a review. Infect Dis Ther. 2017;6(1):69–83.
    65. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966;64(2):328–340.
    66. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018;36(30):3043–3054.
    67. Gudiol C, Aguado JM, Carratalà J. Bloodstream infections in patients with solid tumors. Virulence. 2016;7(3):298–308.
    68. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56–e93.
    69. Ramphal R. Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the currently isolated pathogens. Clin Infect Dis. 2004;39(suppl 1):S25–S31.
    70. Meidani M, Sadeghi SAM. Respiratory viruses in febrile neutropenic patients with respiratory symptoms. Adv Biomed Res. 2018;7:5.
    71. Wood MJ. Viral infections in neutropenia—current problems and chemotherapeutic control. J Antimicrob Chemother. 1998;41(suppl D):81–93.
    72. Youssef J, Novosad SA, Winthrop KL. Infection risk and safety of corticosteroid use. Rheum Dis Clin North Am. 2016;42(1):157–176.
    73. O'Brien SM, Keating MJ, Mocarski ES. Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab. Clin Lymphoma Myeloma. 2006;7(2):125–130.
    74. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99(10):3554–3561.
    75. Jones JA, Robak T, Brown JR, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017;4(3):e114–e126.
    76. Varughese T, Taur Y, Cohen N, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis. 2018;67(5):687–692.
    77. US National Library of Medicine. Zydelig. Accessed June 2, 2020.
    78. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):309–318.

    immunosuppression; asplenia; HIV infection; solid organ transplant; biologic use; cancer

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