Pulmonary Medicine

Pulmonary Infections in the HIV-Negative, Immunocompromised Host

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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 esoteric 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, and kidney and liver function; and the presence of active and immune modulating viruses like cytomegalovirus, HIV, hepatitis C, hepatitis B, and Epstein-Barr virus. Nonetheless, it may be difficult to predict which individual patients are at highest risk for developing new infection or reactivating latent disease.

Classification:

Pulmonary syndromes in immunocompromised hosts may be infectious or noninfectious in etiology. Noninfectious etiologies should always be considered in this population, may have varied clinical syndromes. Important noninfectious etiologies in the HIV-negative, immunocompromised host include rapamycin/sirolimus-induced pneumonitis, graft versus host disease and/or recurrent tumors in hematopoetic stem cell transplant recipients, post-transplant lymphoproliferative disorder (PTLD), acute or chronic rejection in lung transplant recipients, and medication-induced lung injury.

Infectious etiologies range from viruses to bacteria to fungi, with the risk of any particular infection depending on epidemiologic exposure(s); nosocomial factors; and in organ transplant recipients, similar factors in the organ donors. The various infectious etiologies can be categorized into community-acquired infections, nosocomial or ventilator-associated 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 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 of illness. Given the reduced inflammatory response, symptoms of lung 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.

Some symptoms are suggestive of specific etiologies; for example, purulent sputum may be more likely with bacterial infections than with other types of infections, while significant hemoptysis can be seen with invasive fungal infections. In general, it is necessary to send broad diagnostic assays in order to make the correct diagnosis.

Immunocompromised hosts are more likely than the normal population to have atypical infections or unusual manifestations of common infections. It is important to maintain a broad differential diagnosis in this population in order to avoid missing any possible etiologies of pulmonary infections.

Viral pulmonary infections

Routine viruses like adenovirus, respiratory syncytial virus (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, viral infection increases the risk of superinfection with bacteria and fungi.

In solid organ and bone marrow transplantation, cytomegalovirus (CMV) is a significant and common problem. Many solid organ transplant recipients are given prophylaxis for some 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 contributes to the development of bronchiolitis obliterans syndrome (BOS).

Bone marrow 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 also be harder to reduce the immunosuppression, especially in the setting of graft versus host disease (GVHD). Diagnosis of CMV pneumonia can be complicated since people may shed the CMV in their sputum yet do not have pneumonia; therefore, the diagnosis should include the appropriate clinical syndrome, physical exam findings of viral pneumonia, and appropriate radiographic 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 traction is provided, and most experts feel it is better to administer the vaccine than not. 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, some clinicians may 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 that include Nocardia, Rhodococcus, Pseudomonas, Burkholderia, Legionella, MR SA 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. 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; as a result, candida pneumonia is greatly over-diagnosed. Patients with fungal pulmonary infections are more likely than other patients to have hemoptysis, probably because of the angioinvasive nature of filamentous fungi.

Parasitic pulmonary infection

Parasitic pulmonary infections, which are rare in immunocompromised hosts, include toxoplasma, strongyloides (especially in those from endemic areas who reactivate disease in the setting of immunocompromise), 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 rapamycin/sirolimus-induced pneumonitis, graft versus host disease and/or recurrent tumors in hematopoetic stem cell transplant recipients, post-transplant lymphoproliferative disorder (PTLD), acute or chronic rejection in lung transplant recipients, and medication-induced lung injury.

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

Numerous latent pulmonary infections that can reactivate in the immunocompromised setting include 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 start of their immunocompromising medications.

When possible, vaccines should be given before the immunosuppression is begun. Alternatively, they can be given during periods of lower immunosuppression in order 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 immunocompromised host seasonal influenza vaccine (as the injected preparation), polyvalent pneumococcal vaccination (such as the Pneumovax), and protection against diphtheria and pertussis.

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 a variety of infections. When possible, it may be worth trying to desensitize patients to trimethoprim/ sulfamethoxazole.

Certain other immune-compromised hosts, such as those who have undergone lung transplant and who are on ganciclovir or valganciclovir to prevent CMV infection and those who have undergone bone marrow transplant and who are on acyclovir to prevent disseminated herpes zoster, may be on antiviral prophylaxis. During times of heavy influenza activity, some clinicians give their immunocompromised patients oseltamivir, which can mitigate the risk of influenza. Some lung transplant and bone marrow transplant programs give long-term antifungal prophylaxis, which can also 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, bone marrow transplant, or myeloablative chemotherapy). In addition, those with architectural lung abnormalities (i.e., bronchietasis) are at higher risk for infection. Smoking, especially marijuana smoking, can 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 culture should be sent on all patients; if necessary, induced sputum can be obtained using inhaled saline. An upper respiratory specimen may 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, a galactomannan antigen, 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 staining, and cytology and a galactomann antigen.

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, culture, acid fast bacilli stain and culture, modified acid fast bacilli stain (for nocardia and actinomyces), fungal stain and culture, pneumocystis staining, and cytology and a galactomann antigen.

Sometimes the answer may be obvious based on the diagnostics sent. At 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 like bronchoscopy, transbronchial biopsy, CT-guided needle biopsy, and/or even VATS or open thoracotomy.

Numerous studies show that early and broad diagnostics are more likely to result in good outcomes than late and/or narrow diagnostics are. 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.

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 certain 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 have renal insufficiency.

Radiographic findings with fungal pneumonias include nodular disease, and sometimes "halos" are seen, especially with aspergillus. Findings may show cavitating and non-cavitating dense infiltrates; pneumocystis and viral pneumonias commonly have hazy, diffuse, patchy pulmonary infiltrates, while bacterial pneumonias often have segmental or lobar infiltrates.

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?

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 culture should be sent on all patients; if necessary, induced sputum can be obtained using inhaled saline. An upper respiratory specimen may 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, a galactomannan antigen, 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 staining, and cytology and a galactomann antigen.

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, culture, acid fast bacilli stain and culture, modified acid fast bacilli stain (for nocardia and actinomyces), fungal stain and culture, pneumocystis staining, and cytology and a galactomann antigen.

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

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 culture should be sent on all patients; if necessary, induced sputum can be obtained using inhaled saline. An upper respiratory specimen may 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, a galactomannan antigen, 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 staining, and cytology and a galactomann antigen.

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, culture, acid fast bacilli stain and culture, modified acid fast bacilli stain (for nocardia and actinomyces), fungal stain and culture, pneumocystis staining, and cytology and a galactomann antigen.

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

Lung biopsy (open or VATS) is sometimes needed 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.

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 are 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, such as ceftazidime or cefepime. 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. Consultation with an infectious diseases specialist or 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 good, although there is a higher risk of morbidity and mortality in this population than in normal populations. 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 aspergillosis).

What’s the evidence?

Fishman, JA. "Infection in solid-organ transplant recipients". N Engl J Med. vol. 357. 2007. pp. 2601-14.

Hafkin, J, Blumberg, E. "Infections in lung transplantation: new insights". Curr Opin Organ Transplant. vol. 14. 2009. pp. 483-7.

Kotton, CN, Kumar, D, Caliendo, AM. "International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation". Transplantation. 2010.

Kumar, D, Blumberg, EA, Danziger-Isakov, L. "Influenza Vaccination in the Organ Transplant Recipient: Review and Summary Recommendations(dagger)". Am J Transplant. vol. 11. 2011. pp. 2020-30.

"Recommended Adult Immunization Schedule for United States 2012". Morbidity and Mortality Weekly Report (MMWR). 2012. pp. 61. www.cdc.gov/vaccines/recs/schedules/downloads/adult/mmwr-adult-schedule.pdf.

Ruiz-Camps, I, Aguado, JM, Almirante, B. "Guidelines for the prevention of invasive mould diseases caused by filamentous fungi by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC).". Clin Microbiol Infect. vol. 17. 2011. pp. 1-24.

Sassi, M, Ripamonti, C, Mueller, NJ. "Outbreaks of Pneumocystis pneumonia in 2 renal transplant centers linked to a single strain of Pneumocystis: implications for transmission and virulence". Clin Infect Dis. vol. 54. 2012. pp. 1437-44.

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