What every physician needs to know:

Pulmonary infections in HIV-negative, immunocompromised hosts occur frequently and are among the most common infectious complications in these patients. The clinical spectrum of disease is broad, ranging from routine pathogens like Streptococcus pneumoniae and influenza to much more opportunistic infections like invasive aspergillosis, Nocardia, and other rare entities. Understanding the clinical presentations, risk factors, and pertinent diagnostic tests is central to providing optimal care for this vulnerable population.

Immunocompromised patients’ risk of infection correlates with their overall net state of immunosuppression as it relates to immunosuppressive medications (including the dose, duration, and type); the status of the patient’s immune system, underlying disease state and other comorbidities, kidney and liver function; and the presence of active and immune modulating viruses like cytomegalovirus, HIV, hepatitis C, hepatitis B, and Epstein-Barr virus. Regardless, it may be difficult to predict which individual patients are at highest risk for developing new infection or reactivating latent disease.

Classification:

Infectious etiologies range from viruses to bacteria to fungi, with the risk of any particular infection dependent on epidemiologic exposure(s); nosocomial factors; and in organ transplant recipients, donor factors. The various infectious etiologies can be categorized into community-acquired infections, nosocomial pneumonia, and (more rarely) opportunistic infections.

Opportunistic infections can range from atypical pathogens that are rarely, if ever, seen in normal hosts to common infections with highly atypical presentations in immunocompromised hosts. Examples include respiratory syncytial virus (RSV) or adenovirus, which might manifest as an upper respiratory tract infection of minimal consequence in those with normal immune systems but might cause life-threatening disseminated infection in immunocompromised hosts.

Are you sure your HIV-negative, immunocompromised patient has a pulmonary infection? What should you expect to find?

All types of pulmonary infections in immunocompromised hosts may have significant overlap with the common symptoms and signs typically seen in immunocompetent hosts. Given the reduced inflammatory response, symptoms of pulmonary infection may be either more muted compared with those in normal hosts, or they may be more extreme given the higher risk for severe infection in this population.

Viral pulmonary infections

Routine viruses like adenovirus, RSV, parainfluenza, influenza, and others may cause much more severe illness in immunocompromised hosts than in the normal population. These viruses may cause worse pulmonary disease, and some (e.g., adenovirus) may cause disseminated disease. Immunocompromised hosts are at higher risk for pulmonary infection from varicella and herpes viruses, and they have prolonged disease and shedding of virus. In addition to the direct effects of viral infection, importantly, viral infection increases the risk of superinfection with bacteria and fungi.

In solid organ and stem cell transplantation, cytomegalovirus (CMV) is a significant and common problem. Many solid organ transplant recipients are given prophylaxis for a period of time after transplant, which significantly reduces the risk of CMV infection. Some programs choose to use pre-emptive therapy, by which patients are monitored weekly and treatment with antiviral therapy is begun once a certain threshold is reached. Improvement in prevention of CMV has resulted in lower rates of active CMV infection, including reduced rates of pneumonia. Active CMV pneumonia is especially concerning in lung transplant recipients, as they are more likely to have both acute and chronic rejection of the allograft, and many lung transplant experts believe that CMV and other viral infections contribute to the development of bronchiolitis obliterans syndrome (BOS).

Stem cell transplant recipients also develop CMV pneumonia, especially since prophylaxis with ganciclovir or valganciclovir is not well tolerated given the significant risk of myelosuppression. It can be challenging to reduce the immunosuppression, especially in the setting of (GVHD. Diagnosis of CMV pneumonia can be complicated since people may shed the CMV in their sputum without clinical evidence of pneumonia; therefore, the diagnosis should include the appropriate clinical syndrome, physical exam findings of viral pneumonia, and appropriate radiographic, microbiologic, and pathologic findings.

To prevent significant viral infection, it is important that immunocompromised hosts receive the injectable influenza vaccine every year. While the vaccine may not be as immunogenic in immunocompromised hosts as in normal hosts, numerous series show that at least some protection is provided, and most experts feel it is beneficial to administer the vaccine. In addition, hospitalized patients with active viral infections should be placed on droplet precautions to avoid spreading disease to noninfected people. During periods of extensive influenza disease in the community or in a patient’s home, some clinicians may opt to give their immunocompromised hosts preventative antiviral prophylaxis with oseltamivir or other agents.

Bacterial and mycobacterial pulmonary infections

In addition to the routine causes of bacterial pneumonia, immunocompromised hosts are at higher risk than the normal population for infections with atypical pathogens including but not limited to: Nocardia, Rhodococcus, Pseudomonas, Burkholderia, Legionella, MRSA and multi-drug-resistant gram-negative pathogens. In the era of increased antibiotic resistance, it is imperative to make a culture diagnosis so antibiotic sensitivities can direct appropriate management.

Immunocompromised hosts are also at higher risk for developing mycobacterial infections like tuberculosis and–especially in non-endemic areas–non-tuberculous mycobacteria like Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium abscessus, and others. Because of the immunosuppression, drug interactions, and the need for prolonged therapy, management can be arduous in this population. Therapeutic drug monitoring can be helpful in optimizing care, and close clinical and radiographic follow-up can optimize the effectiveness and duration of therapy.

Fungal pulmonary infections

Fungal pathogens, a major concern for immunocompromised hosts, include Pneumocystis; Cryptococcus;endemic fungi like coccidioides, histoplasma, and blastomyces; and filamentous fungal infections like aspergillus, mucormycosis, and scedosporium. The morbidity and mortality from invasive fungal infections is significant especially with the filamentous species. Candida almost never causes invasive pulmonary infection, although many sputum and respiratory cultures are positive for it, probably because of contamination from thrush or simple colonization after broad spectrum antibiotic use. Candida pneumonia is thus greatly over-diagnosed and rarely warrants therapy. Patients with fungal pulmonary infections are more likely than other patients to have hemoptysis, probably because of the angioinvasive nature of filamentous fungi.

Because of the significant morbidity and mortality with invasive fungal infection in immunocompromised hosts, many practitioners prescribe anti-fungal prophylaxis after both solid organ transplant and stem cell transplant.

Parasitic pulmonary infections

Parasitic pulmonary infections, which are rare in immunocompromised hosts, include toxoplasma, Strongyloides (especially in those from endemic areas who reactivate disease when immunocompromised), and Leishmania (again, primarily in endemic areas).

Beware: there are other diseases that can mimic pulmonary infection:

Noninfectious etiologies should always be considered in this population. Important noninfectious etiologies in the HIV-negative, immunocompromised host include graft versus host disease and/or recurrence of disease in hematopoietic stem cell transplant recipients, post-transplant lymphoproliferative disorder (PTLD), acute or chronic rejection in lung transplant recipients, and medication-induced lung injury, i.e. rapamycin-induced pneumonitis.

How and/or why did the HIV-negative, immunocompromised patient develop a pulmonary infection?

Numerous latent pulmonary infections can reactivate in the immunocompromised setting including tuberculosis, coccidiomycosis, histoplasmosis, disseminated strongyloidiasis, toxoplasmosis, and other latent infections. Patients with latent tuberculosis should usually be given appropriate chemoprophylaxis so they do not reactivate their disease. Those with latent coccidiomycosis may benefit from prophylaxis with fluconazole, while those with dormant Strongyloides infection should be given ivermectin or another antiparasitic agent, when possible, before the initiation of immunosuppressive medications.

Vaccines should be given before immunosuppression is started when possible. Alternatively, they can be given during periods of lower immunosuppression to optimize the immunologic response. Live vaccines (such as attenuated intranasal influenza, MMR, varicella/zoster, yellow fever, oral polio, and others) should not be given to immunocompromised hosts. To prevent respiratory infections, it may be prudent to give an immunocompromised host the seasonal influenza vaccine (as the injected preparation), pneumococcal vaccination (such as the Pneumovax and Prevnar vaccines), and protection against diphtheria and pertussis (in the form of a combined vaccine with tetanus).

Certain immunocompromised hosts are given medications to prevent infection, which can alter their risk of developing specific infections. For example, some immunocompromised hosts may be given trimethoprim/sulfamethoxazole to prevent pneumocystis, Nocardia, Streptococcus pneumoniae, toxoplasmosis, and various other pathogens. Patients who are allergic to trimethoprim/ sulfamethoxazole may be given other agents, such as atovaquone, dapsone, or pentamidine, but these are significantly less effective in preventing non-pneumocystis pathogens. When possible, it may be worth trying to desensitize patients to trimethoprim/sulfamethoxazole.

Certain other immunocompromised hosts are on antiviral prophylaxis i.e. those who have undergone lung transplant and who are on ganciclovir or valganciclovir to prevent CMV infection and those who have undergone stem cell transplant and who are on acyclovir to prevent disseminated herpes zoster. During times of heavy influenza activity, some clinicians give their immunocompromised patients oseltamivir, which can mitigate the risk of influenza. Some solid organ transplant and stem cell transplant programs give long-term antifungal prophylaxis, which can reduce the risk of fungal infection.

Which HIV-negative, immunocompromised people are at greatest risk of developing a pulmonary infection?

HIV-negative, immunocompromised people are at greatest risk of developing a pulmonary infection when they are very immunosuppressed (i.e., right after lung transplant, stem cell transplant, or myeloablative chemotherapy). Prolonged high doses of corticosteroids are another important risk factor. In addition, those with architectural lung abnormalities (i.e., bronchiectasis) are at higher risk for infection. Smoking, including marijuana smoking, can also increase the risk of infection. Marijuana smoking can increase the risk of Aspergillus and other molds in this vulnerable population.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Standard laboratory studies in an immunocompromised host with a pulmonary infection should include routine blood work, including an LDH and CBC with differential. Sputum gram stain and bacterial culture should be sent on all patients; if necessary, induced sputum can be obtained using inhaled saline. An upper or lower respiratory specimen should be sent for a respiratory viral panel, which can be done with excellent sensitivity and specificity using molecular diagnostics.

When considering a fungal etiology, clinicians may want to send fungal markers that include a cryptococcal serum antigen, coccidiomycosis serologies, a galactomannan antigen for aspergillus, and a 1,3-beta-D-glucan. In certain situations, especially when the diagnosis is broad, it may be prudent to send sputum for acid fast bacilli stain and culture, modified acid fast bacilli stain (for nocardia and actinomyces), fungal stain and culture, pneumocystis direct fluorescent antibody, galactomann antigen or aspergillus PCR, and cytology.

Urine may be sent for legionella, pneumococcal, and histoplasmosis or coccicidiomycosis antigen testing. When bronchoscopy (with or without a transbronchial biopsy) is performed, broad studies should be sent, including gram stain, bacterial culture, acid fast bacilli stain and culture, modified acid fast bacilli stain (for nocardia and actinomyces), fungal stain and culture, pneumocystis staining, galactomann antigen or Aspergillus PCR, and cytology.

Sometimes the answer may be obvious based on the diagnostics sent. Other times, it may be a combination of clinical findings. For example, the hazy infiltrates of pneumocystis are not usually specific, but when they are combined with an elevated LDH and 1,3 beta-D-glucan, a clinician can feel more certain about the diagnosis. In this vulnerable population, it is always prudent to try to obtain a diagnosis, which may require invasive diagnostics (discussed below).

Numerous studies show that early and broad diagnostics are more likely to result in good outcomes than late and/or narrow diagnostics. Immunocompromised hosts may sometimes have more than one process, and it is possible that they have two or more concomitant infections. If clinicians feel that the diagnostics are not correct in that particular clinical scenario, it is prudent to press on for more confirmatory diagnostic testing.

What imaging studies will be helpful in making or excluding the diagnosis of a pulmonary infection in an HIV-negative, immunocompromised host?

Most immunocompromised patients with pulmonary symptoms have a chest x-ray. It may be helpful for most patients to undergo CT scanning, which is much more sensitive than chest x-ray. In addition, the type of infection may be better defined using the higher resolution of a CT scan than that of a chest x-ray. Intravenous contrast dye is not always needed, especially if one just needs to look at pulmonary parenchyma; it may be helpful to bypass the contrast dye, as many immunocompromised patients also have renal insufficiency.

Radiographic findings with fungal pneumonias include nodular disease, and sometimes “halos” are seen, especially with aspergillus and often represents surrounding hemorrhage. Findings may show cavitating and non-cavitating dense infiltrates. Pneumocystis and viral pneumonias commonly have hazy, diffuse, patchy pulmonary infiltrates and ground-glass opacities, while bacterial pneumonias often have segmental or lobar infiltrates. Despite these commonly described patterns, however, these findings remain non-specific and cannot definitively identify the type of pathogen causing infection in the immunocompromised patient population.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a pulmonary infection in an HIV-negative, immunocompromised host?

Other than the laboratory studies discussed above, no additional non-invasive pulmonary studies are routinely indicated.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a pulmonary infection in an HIV-negative, immunocompromised host?

Bronchoscopy with bronchoalveolar lavage (BAL) and sometimes transbronchial biopsy can be helpful in unclear cases. Specimens can be sent for Gram stain, bacterial culture, mycobacterial stain and culture, fungal stain and culture, pneumocystis stain, galactomannan antigen or Aspergillus PCR, as well as for pathology or cytology. This can be especially helpful in immunocompromised hosts with atypical infections.

Other lung biopsies, obtained via CT-guided needle biopsy, VATS, or open thoracotomy may sometimes be necessary to distinguish between different pulmonary processes. While it is almost never used early, lung biopsy may be helpful in diagnosing the etiology of refractory pulmonary processes including infections. Risks and benefits should be weighed and certain patient populations, i.e. stem cell transplant recipients, may be high risk for invasive procedures.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a pulmonary infection in an HIV-negative, immunocompromised host?

Pathology and cytology studies of sputum, bronchoalveolar lavage, transbronchial biopsy, and lung biopsy material can be helpful in identifying the pulmonary process. In general, pathology and cytology studies are used less often than microbiologic techniques.

If you decide the HIV-negative, immunocompromised patient has a pulmonary infection, how should the patient be managed?

Empiric therapy is often begun in immunocompromised hosts before a diagnosis is obtained. Depending on the clinical manifestations, it may be prudent to initiate therapy with a broad antibacterial agent that includes Pseudomonas coverage. Alternatively, it may be wise to cover atypical causes of pneumonia, as well as MRSA, fungi, and other pathogens, while the workup is in progress. During certain seasons, empiric influenza therapy can also be appropriate. Consultation with an infectious diseases specialist and a pulmonologist may help guide appropriate choices.

Patients with respiratory viral pathogens, MRSA, highly resistant gram-negative bacteria, and even pneumocystis can transmit infection to other people, so infection control is important. Hospitalized patients with respiratory viral infections should be on droplet precautions. Person-to-person transmission of pneumocystis has been documented. In the outpatient setting, it is important to limit the transmission of multi-drug-resistant gram-negative pathogens (Pseudomonas, Burkholderia, and others) and varicella (i.e., with clinical zoster) to nonimmune patients.

What is the prognosis for patients managed in the recommended ways?

Overall, prognosis for immunocompromised hosts with pulmonary infections can be favorable, although there is a higher risk of morbidity and mortality in this population than in normal populations especially in cases of invasive fungal infections. Depending on the individual patient’s response to treatment, treatment may be prolonged and secondary prophylaxis may be used, especially with pneumocystis or other invasive fungal infections.

Lung transplant patients with pulmonary infections, especially soon after transplant, are at higher risk for involvement of the bronchial anastomosis, which can cause dehiscence of the lung graft and may be a life-threatening complication. For this reason, lung transplant programs usually focus on preventing infection and are vigilant about diagnosing and treating infection early.

What other considerations exist for HIV-negative, immunocompromised patients with pulmonary infections?

Immunocompromised hosts with frequent lung infections should be evaluated to determine whether prophylactic agents or vaccines might reduce the risk of subsequent infection. Trimethoprim/sulfamethoxazole can be effective in preventing pulmonary infections that range from bacterial to pneumocystis. Antifungal agents are sometimes used in certain patients to decrease the risk of fungal infection.

Vaccination against pneumococcal disease, influenza, pertussis, and diphtheria may also be effective, as can counseling on infection control, including frequent hand washing, wearing masks when appropriate, and avoiding contact with sick people, construction sites, and marijuana (which can increase the risk of aspergillus infection).

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Pulmonary Infections in the HIV-Negative, Immunocompromised Host