CONTENTS

tests & approaches

• Approach to pulmonary infections
  • Infectious disease history
  • 12 organisms to consider
  • Selected radiological associations
  • Noninvasive infectious evaluation
  • Bronchoscopy: tests to consider
  • Antibiotic selection
• Animal exposures
• Selected diagnostic tests:
  • Beta-D-glucan
  • Galactomannan
  • Atypical lymphocytosis

specific immunocompromising disorders

• HIV
  • Kaposi sarcoma (KS)
  • Pulmonary hypertension due to HIV ➡️
  • IRIS (immune reconstitution inflammatory syndrome)
• Transplantation
• Pulmonary complications related to selected medications:
  • Steroid
  • TNF-inhibitor
  • T-cell depletion
  • B-cell depletion
  • Calcineurin inhibitors (cyclosporine, tacrolimus) ➡️
  • Antimetabolites (mycophenolate, azathioprine, 6-MP, fludarabine)
  • Target of rapamycin inhibitors (sirolimus, everolimus) ➡️
  • Tyrosine kinase inhibitors (ibrutinib, dasatinib)
• Neutropenia
• Lymphopenia
• Hypogammaglobulinemia
• Common variable immunodeficiency (CVID)
  • GLILD (granulomatous and lymphocytic interstitial lung disease)
• CGD (chronic granulomatous disease)
• Hyper-immunoglobulin E syndrome (HIES)

interpreting Gram stain & fungal morphology

• Bacterial Gram-stain morphology
  • Gram-positive
  • Gram-negative
• Fungal morphologies
  • Blastomyces
  • Cryptococcus
  • Histoplasma
  • Coccidioides
  • Candida
  • Aspergillus et al.
  • Mucorales species
  • Dematiaceous fungi
  • PJP (Pneumocystis jirovecii)
  • Penicillium
  • Paracoccidioides brasiliensis
  • Sporothrix

abbreviations used in the pulmonary section: 3

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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approach to investigating pulmonary infection

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infectious disease history

• Travel?
• Animal exposure?
• Residence in TB-endemic country?
• Review prior culture results: drug-resistant organisms?
• Recent healthcare contact? (admission, IV antibiotics?)
• Transplantation?
  • Time since transplant?
  • Prophylactic antibiotic regimen?
• Immunosuppressive medications (including biologics)?

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consider the dirty dozen (especially in immunocompromise)

The following list of pathogens obviously isn't exhaustive. When considering a complex pulmonary infection, it's a reasonable practice to briefly consider whether any of these dozen pathogens could be involved. This list is notably missing atypical pathogens 📖, which should be considered among patients with animal exposure, upper respiratory tract symptoms, and/or extrapulmonary manifestations.

MRSA risk factors 📖

• Radiologic features:
  • Cavitary pneumonia.
  • Septic pulmonary emboli (known or suspected; may relate to chronic PICC or port placement). (31585476)
• Post-influenza pneumonia.
• IV drug use.
• Chronic hemodialysis.
• Skin pustules suggestive of MRSA.
• Known prior/current colonization with MRSA.
• Healthcare contact:
  • Nosocomial pneumonia.
  • Hospitalization with IV antibiotics within three months.

pseudomonas risk factors 📖

• (1) Structural lung disease:
  • Bronchiectasis (especially cystic fibrosis).
  • Prior tracheostomy.
  • Severe COPD, e.g.:
    • FEV1 <30% predicted.
    • Recurrent exacerbations requiring steroid and antibiotic use. (32561442)
• (2) Immunosuppression:
  • Neutropenia/hematologic malignancy.
  • HIV with CD4 count <50/uL.
• (3) Prior colonization/infection with Pseudomonas. (34481570)
• (4) Broad-spectrum antibiotics for >7 days within past month.
• (5) Nosocomial acquisition of infection.

pneumocystis risk factors 📖

• (1) HIV with CD4 count <200/uL.
• (2) Steroid (>90% of non-HIV PJP).
  • Risk increases after ~15 mg/day for two months.
  • Especially high risk:
    • Steroid + glioblastoma.
    • Steroid + rheumatologic disease.
    • Steroid + other immunosuppressives.
• (3) Malignancy:
  • Hematologic malignancy (especially acute leukemia, non-Hodgkin lymphoma).
  • Chemotherapy (listed below).
• (4) Solid organ transplantation (~10% risk; typically 4-6 months post-transplant).
• (5) Immunosuppressive medications:
  • Alkylating agents (cyclophosphamide, temozolomide).
  • Anti-metabolites (methotrexate, cytarabine, fluorouracil).
  • Purine analogs (azathioprine, cladribine, fludarabine, mycophenolate mofetil).
  • Calcineurin inhibitors (cyclosporine, tacrolimus).
  • mTOR inhibitors (everolimus, sirolimus, temsirolimus).
  • TNF-alpha inhibitors (e.g., adalimumab, certolizumab, etanercept, infliximab, golimumab).
  • IL-6 inhibitors (sarilumab, tocilizumab).

CMV risk factors 📖

• Stem cell transplantation:
  • CMV is most common viral illness, especially 1-3 months post transplant.
  • Overall risk is considerable (~20%).
  • Risk factors: seropositivity of donor and/or recipient; allogeneic stem cell transplantation; acute graft-versus-host disease.
• Solid organ transplantation: CMV is common, especially 1-6 months post transplant.
• HIV: CMV pneumonia is more likely when the CD4 count <50/uL.

HSV risk factors 📖

• Transplantation:
  • Usually within the first few months post transplantation.
  • HSV is less common than CMV (~5% risk).
• Immunosuppressive medications.
• Malignancy, chemotherapy.
• HIV: HSV pneumonia is rare, might be associated with lower CD4 counts (e.g., <200/uL).

invasive aspergillosis risk factors 📖

• Neutropenia (especially prolonged >10 days).
• Steroid use (especially high-dose or prolonged).
• Transplantation, usually during the first post-transplant year: (16110792)
  • Lung transplant (2.4%) – most common invasive fungal infection following lung transplant. (30900275).
  • Heart transplant (0.8%).
  • Liver transplant (0.3%).
  • Kidney transplant (0.1%).
• Malignancy:
  • Treated with cytotoxic chemotherapy.
  • Treated with ibrutinib (inhibitor of Bruton tyrosine kinase). (Murray 2022)
• Influenza:
  • May complicate ~5-10% of severe influenza.
  • May be diagnosed relatively soon (3-5d after admission). (34366041)

mucormycosis risk factors 📖

• (1) Hematological malignancy (~70% cases), especially associated with: (36983475)
  • Acute leukemia.
  • Prolonged neutropenia.
  • Voriconazole or echinocandin prophylaxis.
• (2) Organ transplantation (~15% cases). (36983475)
  • Mucormycosis may cause a breakthrough infection in stem cell transplant recipients on voriconazole treatment/prophylaxis. Graft-versus-host disease is a risk factor. (33965160)
• (3) Diabetes, especially diabetic ketoacidosis (DKA):
  • Patients with DKA may develop rapidly progressive or indolent mucormycosis. Sinus disease is more common in DKA, but pulmonary infection can also occur.
  • Diabetes is the sole risk factor in up to a third of patients with pulmonary mucormycosis. (31042090)
• (4) Steroid use
  • This includes COVID-associated mucormycosis. (35000717) The major risk factors for COVID-associated mucormycosis include poorly controlled diabetes and steroid use. This usually emerges about 2-3 weeks after initial COVID diagnosis. (35396054) 
• (5) Deferoxamine therapy.

cryptococcus risk factors 📖

• (1) HIV:
  • Cryptococcus is the most common fungal infection in people with HIV.
  • CD4 count is usually <100-200/uL.
• (2) Solid organ transplantation
  • Cryptococcosis is the third most common invasive fungal pathogen in solid organ transplant patients (after Candida and Aspergillus). (Murray 2022)
  • Cryptococcus is often a relatively late complication of solid organ transplantation, occurring a median of ~1.5 years post-transplant. (26540422)
• (3) Immunosuppressive medications, including:
  • Chronic steroid use.
  • TNF-inhibitors.
  • Azathioprine.
  • Calcineurin inhibitors (e.g., cyclosporine, tacrolimus).
  • Fingolimod (an S1P receptor modulator used for multiple sclerosis).
  • Tyrosine kinase inhibitors (e.g., ibrutinib). (33516057, 33896533)
• (4) Malignancy (especially hematological).
• (5) No underlying immunocompromising condition (~15-50% of patients). (30329097) Patients may have mild immunocompromising conditions (e.g., cirrhosis, diabetes, renal failure). 

blastomycosis risk factors 📖

• Most patients are immunocompetent.
• Risk factors for more severe disease:
  • Transplantation.
  • HIV with CD4 count below ~200/uL. (Murray 2022)
  • Immunosuppression (especially chronic steroid use, TNF-inhibitors).
  • Malignancy.
  • Diabetes.

histoplasmosis: risk factors for rapidly progressive/disseminated infection 📖

• HIV (especially with CD4 count <100-150/uL). (34498137) 
• Transplantation (especially solid organ transplantation). After solid organ transplantation, donor-related infection and reactivation of latent histoplasmosis are the most common mechanisms (rather than de novo infection). Infection onset has a bimodal distribution, often occurring <6 months after transplantation, or >2 years afterwards. (28797485)
• Hematologic malignancy.
• Immunosuppressive medications, especially:
  • Chronic steroid therapy.
  • TNF-inhibitors (histoplasmosis is the most common invasive fungal disease in this context). (32000281)
  • Bruton tyrosine kinase inhibitors (acalabrutinib, ibrutinib, zanubrutinib).
  • Lymphodepleting agents (especially alemtuzumab).
• High intensity exposure: closed space with high concentration of Histoplasma (e.g., cleaning chicken coop or attic).

tuberculosis risk factors 📖

• Exposure:
  • [1] Geography:
    • Born in a country with high TB rates (may be the strongest risk factor).
    • Lived in an endemic area.
    • Extensive travel to a highly endemic area.
  • [2] Personal history of tuberculosis.
  • [3] Close contacts with active tuberculosis.
• Risk factors for reactivation/progression:
  • HIV (increases risk ~50-100 fold).
  • Transplantation (increases risk ~50 fold).
  • Chronic renal failure (increases risk ~15-fold).
  • TNF-inhibitors (increases risk ~5-fold, more discussion: 📖). (ERS handbook 3rd ed.)
  • Diabetes (increases risk ~3-fold). (Murray 2022)
  • Other immunosuppressive medications (e.g., >15 mg/day prednisone for >1 month).
  • Malignancy (especially hematologic).
  • Alcoholism.
  • Older age.
  • Malnutrition.

nocardia risk factors 📖

• Cancer therapy: The risk for Nocardia infection seems to result from treatments for cancer (e.g., chemotherapy, steroid, stem cell therapy). Effects of alemtuzumab or purine analogs can persist for months to a few years after administration. (36314911)
• Transplantation:
  • Risk depends on the organ transplanted: (36314911, 33376366)
    • Heart or lung: 1-3.5% risk.
    • Kidney or liver: <1% risk.
  • Additional risk factors for nocardiosis in this population:
    • High trough levels of calcineurin inhibitor.
    • High steroid dose.
    • CMV infection within the preceding six months.
  • The risk of infection is greatest soon after transplant, but ~15% of infections might occur >5 years after transplantation. (36314911)
  • Note that prophylactic use of trimethoprim-sulfamethoxazole does not reliably prevent Nocardia infection. (32629491)
• Therapeutic immunosuppression:
  • Chronic steroid use (even doses as low as 10-15 mg/day prednisone increase risk). (Fishman 2023)
  • TNF-inhibitors.
  • Tocilizumab. (32629491)
• HIV (CD4 count <100-200/uL). (33418019)
• Structural lung disease (especially combined with oral/inhaled steroid): (32629491; 33376366)
  • Bronchiectasis.
  • Advanced COPD.
  • Silicosis.
  • Pulmonary fibrosis.
• Apparently healthy patients (~0-20% of patients).

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selected radiological associations 

predominant diffuse GGO (ground-glass opacity) 📖

• Pneumocystis. 📖
• Viral pneumonias, including:
  • Herpesviruses:
    • CMV. 📖
    • HSV. 📖
  • COVID. 📖
  • RSV. 📖

pleural effusion

• Bacterial pneumonia.
• Tuberculosis.
• Cryptococcus neoformans.
• (Consider thoracentesis of any sizable or radiographically complex/loculated effusion.)

tree-in-bud nodules 📖

• Bacterial or viral bronchopneumonia. 📖
• Mycobacteria (M. tuberculosis or non-tuberculous mycobacteria).
• Fungi:
  • Endemic fungi.
  • Cryptococcus.
  • Aspergillus with tracheobronchial involvement.

macronodules 📖

• Fungal infection:
  • Endemic fungi.
  • Cryptococcus.
  • Mold (e.g., Aspergillus, Mucorales spp.).
• Nocardia infection. 📖
• Septic pulmonary emboli. 📖
• Round pneumonia. 📖
• Atypical pneumonias: Tularemia, Q-fever.
• Mycobacteria (M. tuberculosis or nontuberculous mycobacteria).

cavitation 📖

• Common bacteria:
  • Necrotizing pneumonia. 📖
  • Septic pulmonary emboli. 📖
  • Lung abscess. 📖
• Fungi:
  • Mold:
    • Invasive pulmonary aspergillosis. 📖
    • CCPA (chronic cavitary pulmonary aspergillosis).
    • Mucormycosis.
  • Cryptococcus. 📖
  • Dimorphic fungi:
    •  Coccidioidomycosis:
      • Acute pulmonary cocci cavitates in ~5%. 📖
      • Chronic cavity may also occur. 📖
    • Histoplasmosis, chronic pulmonary. 📖
    • Blastomycosis, chronic. 📖
• Mycobacteria:
  • M. tuberculosis, post-primary. 📖
  • Nontuberculous mycobacteria. 📖
• Nocardia. 📖
• Actinomyces. 📖
• Rare:
  • Rhodococcus equi. 📖
  • Tularemia. 📖
  • Tracheobronchial papillomatosis. 📖
  • Echinococcus. 📖

lymphadenopathy 📖

• Mycobacteria:
  • M. tuberculosis (primary tuberculosis).
  • Nontuberculous mycobacteria (NTM).
• Fungus:
  • Most frequently histoplasmosis or coccidioidomycosis.
  • Less commonly blastomycosis or cryptococcosis. (32433841)
• Bacteria (primarily atypical organisms):
  • Tularemia.
  • Yersinia pestis (plague).
  • Anthrax.
  • Psittacosis.
  • Coxiella burnetii (Q fever).
  • Mycoplasma pneumoniae.
• Viral:
  • EBV (Epstein Barr virus).
  • VZV (varicella zoster virus).
  • Influenza H1N1.

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non-bronchoscopic workup for pulmonary inflammatory/infectious diseases: possible tests 

CT chest

• CT scan is the fundamental investigation for pneumonia, especially in immunocompromise.
• Pattern of CT scan abnormalities may narrow the differential diagnosis and direct subsequent investigation. Thus, CT scan should be obtained early.

blood, urine, & nasopharyngeal PCR tests

• Complete blood count with differential:
  • ? Eosinophilia.
  • ? Atypical lymphocytosis. 📖
  • ? NLR (neutrophil/lymphocyte ratio). 🌊
• Inflammatory markers:
  • CRP level.
  • Procalcitonin.
• HIV serology.
• Bacteria:
  • Blood cultures.
  • Urine pneumococcus & Legionella antigens.
  • Nasopharyngeal MRSA PCR.
• Fungi:
  • Serum beta-D-glucan.
  • Serum cryptococcal antigen (CrAg).
  • Urinary Histoplasma antigen.
  • Urinary Blastomyces antigen.
  • Serum galactomannan (more useful in neutropenia).
• Virus:
  • Nasopharyngeal PCR:
    • COVID.
    • RSV & influenza.
    • Extended respiratory virus panel.
  • Blood CMV PCR.

sputum analysis

• Spontaneous sputum production or endotracheal aspirate:
  • Bacterial Gram stain & culture.
  • AFB (acid-fast bacilli) stain & culture, +/- tuberculosis PCR.
  • Fungal stain & culture.
  • Nocardia stain & culture (requires a separate order).
  • Pneumocystis PCR.
  • Sputum cytology.
• Sputum induction may be utilized for:
  • AFB (acid-fast bacilli) stain/culture +/- tuberculosis PCR.
  • Pneumocystis PCR.

thoracentesis

• Effusion size and complexity may help evaluate the risk/benefit of pleural sampling.
• Pleural fluid culture yield may increase to 60% when inoculated directly into blood culture bottles. (32034433)

biopsy of readily available lesions:

• Consider punch biopsy of any skin lesion.
• Nodular lesions: transthoracic needle biopsy may be considered, especially for larger lesions that abut the pleura.

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bronchoscopy: tests to consider 

basic tests for all patients:

• Trifecta of cultures & staining:
  • (1) Bacterial culture & Gram stain.
  • (2) Fungal culture & Gram stain.
  • (3) AFB (Acid-Fast Bacilli) stain & mycobacterial culture.
• Differential cell count.
• Cytology (e.g., to evaluate for viral cytopathic effects, fungal infection).

tests to consider selectively:

• Pneumocystis:
  • Cytological staining (more sensitive in HIV than non-HIV).
  • PCR.
• Aspergillus:
  • Aspergillus PCR. 📖
  • BAL galactomannan. 📖
• Tuberculosis PCR.
• Nocardia stain and culture (must be ordered specifically).
• Multiplex PCR for community-acquired respiratory viruses.
• Herpesviruses: Obtain only if suspicion (CMV and HSV generate lots of false-positives).
  • CMV PCR. 📖
  • HSV PCR. 📖
  • VZV PCR. 📖
• PCR testing for atypical pathogens:
  • Legionella.
  • Mycoplasma.

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empiric antibiotic therapy for complex pulmonary infections

The following approach isn't optimal for every pulmonary infection, but it is often a reasonable place to start. 

(1) atypical coverage

• Atypical coverage is generally advisable for most community-acquired pneumonias.
• Doxycycline 💉 is generally preferred over azithromycin, given a broader range of coverage (doxycycline versus azithromycin selection is discussed here: 📖).

(2) backbone coverage for typical pathogens

• Ceftriaxone is often utilized for community-acquired pneumonias.
• Cefepime or piperacillin-tazobactam may be utilized to cover Pseudomonas or drug-resistant organisms (risk factors for Pseudomonas are listed above). Meropenem could be considered for patients at the highest risk of resistant organisms.
• Ceftaroline could be utilized to provide coverage for MRSA (discussed further below).
• Trimethoprim-sulfamethoxazole could be used if there is relatively low suspicion for a typical bacterial pathogen combined with concern for pneumocystis. Trimethoprim-sulfamethoxazole provides reasonable coverage for typical pathogens (e.g., pneumococcus, MSSA, gram-negatives), while simultaneously covering Pneumocystis.
  • {Doxycycline + trimethoprim-sulfamethoxazole 10 mg/kg/day in divided doses + steroid} provides coverage for atypical pathogens, typical bacteria, pneumocystis, and some MRSA activity (both doxycycline and trimethoprim-sulfamethoxazole are active against MRSA, but it should be noted that their ability to treat MRSA pneumonia remains unclear).

(3) MRSA coverage?

• Risk factors are listed above.
• Treatment options include vancomycin, linezolid, or ceftaroline. Further discussion regarding the selection of an anti-MRSA antibiotic is here: 📖

(4) Pneumocystis coverage?

• Indications to consider Pneumocystis coverage include:
  • (1) CT scan is consistent with Pneumocystis.
  • (2) Epidemiological risk factors for pneumocystis: 📖
• Pneumocystis coverage is usually achieved with trimethoprim-sulfamethoxazole combined with steroid therapy (more on the treatment of Pneumocystis here: 📖).

(5) fungal pneumonia coverage?

• Indications to consider fungal coverage include:
  • Severe immunosuppression (especially neutropenia).
  • Radiological pattern suggestive of fungal pathogens (e.g., nodules, cavitation, halo sign, meniscus sign).
• Options:
  • Voriconazole or isavuconazole are generally favorable options which are relatively nontoxic. Isavuconazole offers broader coverage to include mucormycosis if this is a concern (e.g., among patients with diabetes or neutropenia).
  • Amphotericin provides broad coverage but is nephrotoxic, so this should usually be avoided unless there is a very high index of suspicion for fungal infection.
  • ⚠️ Echinocandins are used for empirical coverage of candidemia, but they are usually not preferred agents against fungal pneumonia.

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animal exposure associations with pulmonary pathogens

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The following associations aren't exhaustive, but may represent some entities to include in a differential diagnosis. 

dogs

• Pasteurella spp.
• Coxiella burnetii.
• Bordetella bronchiseptica.
• Brucella spp.
• Capnocytophaga canimorsus.

cats

• Pasteurella spp. (cat cuddler cough)
• Francisella tularensis.
• Bartonella henselae.
• Toxoplasma gondii.
• Bordetella bronchiseptica.

birds/poultry

• Cryptococcus spp.
• Psittacosis.
• Histoplasma capsulatum.
• Avian influenza (poultry).

horses

• Rhodococcus equi.
• Coxiella burnetii.

rabbits

• Bordetella bronchiseptica.
• Francisella tularensis.
• Pasteurella multocida.

rodents

• Francisella tularensis.
• Hantavirus (primarily rodent droppings).
• Yersinia pestis.
• Leptospirosis.

bats

• Histoplasma capsulatum.

other

• Various (cattle, sheep, goats, etc.) – Coxiella burnetii, Bacillus anthracis, Brucella sp.

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serum beta-D glucan

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which fungi contain beta-D-glucan

• Beta-D glucan is a cell wall component present in most fungi, including:
  • Pneumocystis.
  • Candida.
  • Histoplasma, Coccidioides.
  • Aspergillus, Fusarium, Acremonium, Trichosporon, Scedosporium, Saccharomyces.
• Some fungi don't produce significant amounts of beta-D glucan:
  • Blastomyces.
  • Cryptococcus (although beta-D glucan may be detectable in some patients with disseminated disease). (Fishman 2023)
  • Mucorales spp. (including Mucor and Rhizopus).

causes of false-positives

• (1) Medical interventions involving cellulose membrane exposure:
  • Administration of blood products, albumin, or IVIG (intravenous immunoglobulin). The processing of these products involves cellulose exposure.
  • Hemodialysis using cellulose-containing filters.
  • Wound care using gauze packing or sponges. (Murray 2022)
  • 💡In these cases, the beta-D-glucan levels will often fall rapidly after exposure has ceased. Thus, a repeat test may be negative. (31729203)
• (2) Pathogens:
  • Heavy colonization with Candida or mold, predominantly in combination with mucositis. (30561560, 31729203) 
  • Infection with certain bacteria that contain beta-glucans (e.g., Streptococcus spp. or some Gram-negative rods such as Pseudomonas spp.). (18540808) However, false positives due to bacteremia are rare, so the presence of an underlying fungal infection should still be suspected. (31729203)
• (Note: the assay is not affected by piperacillin-tazobactam.) (33044240)

causes of false-negatives

• Hyperpigmented serum (bilirubin, triglyceride).
• Azithromycin or intravenous pentamidine. (31729203)

overall comments on beta-D-glucan

• Overall performance for invasive fungal infection (excluding Pneumocystis):
  • Beta-D-glucan is ~77% sensitive and ~85% specific for an invasive fungal infection. (31729203) 
  • If two consecutive positive results are required, this increases specificity a lot (99% in one study), but also reduced sensitivity to 50%. (31729203)
• 💡 A positive beta-D-glucan assay must be considered very thoughtfully within the context of the individual patient, their immune status, possible causes of false-positive results, and their radiology (e.g., thoracic CT scan). (31585478)

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beta-D-glucan performance for the diagnosis of various specific pathogens

diagnosis of Pneumocystis in HIV(-) patients

• Standard cutoff value (>80 pg/ml) had a sensitivity of ~86-88% and a specificity of ~83-85%. (30561560, 32479781)
• High cutoff value (>200 pg/ml) had a sensitivity of 70% and specificity of 100%. In the presence of a positive PCR, this strongly argues for invasive disease (rather than colonization). (30561560)

diagnosis of Pneumocystis in HIV(+) patients

• Overall, the performance of beta-D-glucan is somewhat better in HIV(+) patients since they usually have a greater burden of organisms.
• The largest study involves the analysis of 252 patients with AIDS and opportunistic infections: (21690628)
• Among all patients, 173/252 patients were diagnosed with PJP:
  • Patients with PJP had beta-D-glucan levels with a median of 408 pg/ml (IQR 209-500 pg/ml).
  • Patients without PJP had beta-D-glucan levels with a median of 37 pg/ml (IQR 31-235 pg/ml).
  • A cutoff value of 80 pg/mL yielded a sensitivity of 92% and a specificity of 65%.
• Among patients presenting with respiratory symptoms, 139/159 patients were diagnosed with PJP. (23698062) A cutoff value of 80 pg/ml yielded a sensitivity of 93% and a specificity of 75%.

diagnosis of invasive pulmonary Aspergillus

• Overall: beta-D-glucan shouldn't be used as the sole test, but it may be useful in combination with galactomannan. (ESCMID18)
• Sensitivity for invasive pulmonary aspergillosis:
  • Sensitivity is ~75%. (31970725)
  • Sensitivity is not reduced by the use of antifungal agents. Beta-D-glucan has better sensitivity than galactomannan among patients who aren't neutropenic.
• Specificity will vary depending on the clinical context. Beta-D-glucan is less specific for aspergillosis. In a clinical scenario suggestive of invasive aspergillosis, a positive result may have reasonable specificity (perhaps ~80%). (31970725) Various causes of a positive beta-D-glucan assay are listed above.

diagnosis of candidemia 

• For ICU patients with suspected invasive candidemia, the sensitivity and specificity of beta-D-glucan are ~80% (with lower performance for focal intra-abdominal infections). This makes BDG potentially useful in septic ICU patients with suspected candidemia. However, if BDG is broadly applied to patients with a low pretest probability of Candida infection, it will lead to a high rate of false-positive results. (29376927)
  • Using a cutoff value >80 pg/mL may improve sensitivity, potentially yielding the best overall test performance.
  • Using a cutoff value >200-250 pg/mL will improve specificity.

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galactomannan

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basics

• This is also known as “aspergillus antigen.”
• Galactomannan is a polysaccharide found in the cell walls of some fungal species (similar to beta-D-glucan).
• Clinically, galactomannan is used to diagnose invasive aspergillosis.

sensitivity for invasive pulmonary aspergillosis

• The most common cutoff is >0.5 index. Some European guidelines recommend a cutoff of >1.0 optical density index, but these practitioners also have access to a broader range of aspergillus tests than are available in the United States (including PCR). (33709125)
• Severely neutropenic patients:
  • This cutoff yields a sensitivity of ~75% and a specificity of ~85%. (ATS guideline 2019)
  • Sensitivity is best when the absolute neutrophil count is <100 cells/uL. (30048345)
• Non-neutropenic patients: sensitivity is lower (perhaps ~50%) because circulating neutrophils will clear the galactomannan antigen. (30299367) 

specificity

• Overall specificity is good (~90%) for Aspergillus.
• Causes of elevated galactomannan levels include:
• [1] Fungal infection:
  • Aspergillus.
  • Cryptococcus.
  • Blastomyces, Histoplasma.
  • Alternaria spp., Acremonium spp., Fusarium spp. , Geotrichum, Trichosporon, Paecilomyces, Penicillium spp. (now renamed Talaromyces), and Wangiella dermatitidis. (36836246)
• [2] Other causes of elevated galactomannan:
  • Some blood transfusion bags.
  • IVIG (intravenous immunoglobulin). (32561442)
  • Flavored ice pops.
• (Historically, piperacillin-tazobactam and playmate have caused false-positive results, but currently, this isn't an issue). (ATS guideline 2019, 38228164)

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BAL galactomannan for diagnosing invasive pulmonary aspergillosis

• The most commonly used cutoff, as recommended by the manufacturer, is >0.5 optical density index. This yields a sensitivity of 79% with a specificity of 84%. (ATS guideline 2019) Some European guidelines recommend a cutoff of >1.0 optical density index, but these practitioners also have access to a broader range of aspergillus tests than are available in the United States (including PCR). (33709125)
• Sensitivity:
  • The sensitivity of BAL galactomannan is superior to serum galactomannan. (31729203)
  • Sensitivity may be especially high among non-neutropenic patients, in whom infection is centered on the airways. (32140409; 31361683) In one series of patients with post-influenza aspergillosis, sensitivity was 94%. (30299367)
• Specificity:
  • Specificity remains good (~80-90%). (38228164, 36836246)
  • BAL galactomannan can be somewhat elevated in patients with Aspergillus or Penicillium colonization. (32572532)
  • Among neutropenic patients, other filamentous molds may need to be considered (e.g., Fusariosis; see list above). (38286175)

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atypical lymphocytosis

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Atypical lymphocytosis is sometimes defined as >10% of lymphocytes appearing as atypical lymphocytes. However, lower numbers of atypical lymphocytes may still provide a useful diagnostic clue. More common causes include the following:

• A broad range of viral infections, especially:
  • Herpesviruses, especially:
    • Mononucleosis (EBV).
    • CMV.
  • Acute HIV.
  • COVID.
  • Parainfluenza virus. (27250631)
  • Viral hepatitis.
  • Rubella, rubeola, dengue virus. (34379819)
• Some non-viral infections:
  • Leptospirosis. (17051497) 
  • Toxoplasmosis.
  • Babesiosis, malaria.
  • Pertussis. (34379819)
  • Histoplasmosis (rarely). (28070489)
• Medications, often as a component of DRESS syndrome. 📖
• Incorrect diagnosis of atypical lymphocytes (e.g., blasts may be incorrectly categorized as atypical lymphocytes by some automated hemocytometers.)

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pulmonary complications of HIV

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⚠️ Among patients with low CD4 counts, radiographic patterns are frequently atypical (compared to usual patterns observed among immunocompetent patients).

bacteria

• Typical bacterial pathogens may occur regardless of CD4 count. In the modern era of antiretroviral therapy, this is the most common cause of respiratory infection – especially encapsulated bacteria. (Shepard 2019; Walker 2019) 
  • (#1) Streptococcus pneumoniae is especially common among people with HIV (with increased rates of bacteremia).
  • (#2) Haemophilus influenzae.
  • (#3) Staphylococcus aureus (especially in the context of septic pulmonary emboli due to intravenous drug use).
  • Klebsiella pneumoniae.
  • Legionella is much more common than in the general population.
• Pseudomonas can occur with CD4 <50-100/uL (especially in combination with recent hospitalization, neutropenia, or broad-spectrum antibiotic use). (Murray 2022)
• Rhodococcus equi (CD4 <100-200/uL). 📖
• Nocardia spp. 📖

mycobacteria

• Tuberculosis: 📖
  • Pulmonary tuberculosis (any CD4 count; but increased with CD4 <500/uL).
  • Disseminated/extrapulmonary tuberculosis (e.g., miliary TB)(CD4 <200/uL).
• Nontuberculous mycobacteria: 📖
  • Disseminated Mycobacterium avium complex (MAC) may occur with very low CD4 counts (<50/uL).
  • Mycobacterium kansasii is usually associated with CD4 <100/uL. (Murray 2022)

viral pneumonia

• Usual community-acquired respiratory viruses (e.g., influenza) are most frequent.
• CMV (CD4 <50/uL). 📖
• HSV (CD4 <100/uL). 📖

fungal pneumonia

• Pneumocystis (CD4 <200/uL). 📖
• Cryptococcus is the most common fungal infection (usually CD4 <200/uL). 📖
• Endemic mycoses: Focal disease is more common when CD4 >200/uL, whereas disseminated disease may be more common when CD4 <200/uL.
  • Progressive disseminated histoplasmosis: 📖
  • Disseminated coccidioidomycosis: 📖
  • Blastomycosis is more virulent, so it's less closely associated with HIV. 📖
• Aspergillosis is uncommon in HIV (e.g., may be seen with CD4 <50-100/uL, and with neutropenia due to ganciclovir). 📖

protozoa/parasite

• Toxoplasma gondii (rare, usually CD4 <50/uL). 📖
• Strongyloides. (32561442)

malignancy

• KS (Kaposi sarcoma) (usually CD4 <50-100/uL). 📖
• Non-Hodgkin lymphoma (CD4 <100-200/uL).
• Primary effusion lymphoma.
• Lung cancer (mostly adenocarcinoma):
  • HIV causes a large increase in the risk of lung cancer (even when the CD4 count is preserved). The incidence of lung cancer among people living with HIV is increasing, due to improvements in lifespan.
  • Histologic types and stages of disease at diagnosis are similar to other patient populations.

interstitial lung disease

• LIP (lymphocytic interstitial pneumonitis; with variable CD4 count).
• NSIP (nonspecific interstitial pneumonitis):
  • May resemble PJP, but the CD4 count is usually much higher (>200/uL).
  • HIV-related NSIP usually stabilizes or resolves without therapy, so only observation is necessary. (Murray 2022)
• COP (cryptogenic organizing pneumonia; with any CD4 count).
• HP (hypersensitivity pneumonitis; usually CD4 >350/uL).
• Sarcoidosis (usually CD4 >200/uL).

other lung diseases

• PAH (pulmonary arterial hypertension). 📖
• Mediation-induced lung disease.
• Emphysema.
• Pulmonary embolism (~2-10 fold increased risk of venous thrombosis). (Walker 2019)

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Kaposi sarcoma (KS)

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basics

• Kaposi sarcoma (KS) is a multicentric, angioproliferative neoplasm consisting of multiple vascular nodules. It is associated with human herpesvirus 8 (HHV8).
• KS is most often associated with either HIV or organ transplantation.
• Dynamics of KS:
  • (1) Patients with pulmonary KS who develop an opportunistic infection may experience accelerated progression of their KS, mimicking an infection. (Murray 2022)
  • (2) IRIS (immune reconstitution syndrome) may exacerbate KS, sometimes causing death. This may result from proinflammatory cytokines up-regulating angioproliferative and tumorigenic factors. (24047065) 

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epidemiology

• KS occurs in ~15% of AIDS patients (although it may be decreasing over time).
• ~95% of cases occur in men who have sex with men.
• CD4 count:
  • KS may occur at any stage of HIV infection.
  • Usually it occurs with CD4 count <50-100/uL.

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symptoms

Skin, lymph nodes, gastrointestinal tract, and lung are the organ systems most often affected (but virtually every organ can be involved).

pulmonary involvement (~33%; clinically apparent in 15%)

• Usual symptoms may include dyspnea, dry cough, and fever.
• ~85% of patients with pulmonary disease have dermatological signs, which usually precede the pulmonary involvement.
• Pleural KS may cause large effusions.
• Airway involvement is usually asymptomatic, but may cause obstruction or hemoptysis. (Shepard 2019)

skin lesions:

• Seen in ~60% of patients.
• Pink to deep purple/brown lesions reflect extravasation of erythrocytes into the skin.
• Initial macules may eventually become thickened plaques and nodular tumors.
• Single lesions or clusters of lesions may occur.
• Location:
  • Most often involve face and legs.
  • Palms are spared.

oral lesions:

• The hard palate is the most common site, followed by the gingiva.
• Usually flat, asymptomatic patches or plaques are noted, which may eventually form nodules. Eventually nodules may ulcerate, bleed, and interfere with swallowing and speech.
• Palatal involvement strongly predicts the presence of pulmonary lesions. (ERS handbook 3rd ed.)

gastrointestinal involvement (50% of patients):

• Involvement of the stomach and small intestine may cause bleeding, hemorrhage, diarrhea, or even perforation.
• Infiltration of the gallbladder and biliary tree may cause obstructive jaundice.
• Hepatic KS is the most common hepatic neoplasm in AIDS patients (causing numerous hypoattenuating lesions on CT scan).

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thoracic radiology

(#1/2) Interstitial thickening:

• Bronchovascular and interlobular septal thickening is seen on CT scan.
• Nodular thickening of bronchovascular bundles may occur.
• Often there is a perihilar distribution.

(#2/2) Diffuse nodular opacities:

• Nodules tend to be:
  • 1-2 cm.
  • Irregular and ill-defined (“flame-shaped”). A surrounding rim of ground-glass opacity can occur (halo sign), which may represent hemorrhage. (Shepard 2019)
• Distribution:
  • Mid- to lower-lung predominant.
  • Often in a perihilar and peribronchovascular distribution.
• With progression, this may mimic the patchy opacities of bronchopneumonia (causing areas of consolidation in a perivascular distribution, especially in the mid- and lower-lung zones).
• In later stages, conglomerate masses and effusions may be present.

additional features which are commonly seen:

• Hilar lymphadenopathy is common, but not bulky. Attenuation on CT scan may be relatively high following contrast injection, due to the vascular nature of KS.
• Effusions are seen in most patients and may be large.
• Endobronchial disease may cause atelectasis or post-obstructive pneumonia. (Shepard 2019) 

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labs – pleural fluid analysis

• Most effusions are bloody or serosanguinous.
• Most effusions are exudative (LDH is typically ~100-300 IU/L).
• Effusions are usually lymphocyte predominant.
• Cytology is non-diagnostic. Even pleural biopsy tends to be unhelpful, because disease is located on the visceral pleura (whereas biopsy samples the parietal pleura).

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bronchoscopy

• Endobronchial lesions may be seen in roughly half of patients with pulmonary KS.
• Appearance of endobronchial KS:
  • Violaceous flat to slightly raised patches.
  • Commonly found at airway bifurcations.
• ⚠️ Endobronchial biopsy should be avoided, since lesions are vascular and tend to bleed.

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differential diagnosis includes:

• KS plus a simultaneous opportunistic infection (seen in ~1/3 of patients with KS). (Murray 2022)
• Lymphoma (especially for oral lesions).
• Multicentric Castleman disease.
• Bacillary angiomatosis (may cause similar skin lesions).
• Cutaneous mycobacterial infections.

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management

• Antiretroviral therapy is the cornerstone of therapy. In most cases, treatment of HIV will cause regression of the KS. This is associated with a relatively high risk of IRIS (immune reconstitution inflammatory syndrome) following the initiation of antiretroviral therapy.
• In some cases, localized or systemic chemotherapy or radiotherapy may be utilized (e.g., progressive KS in the context of IRIS). (24047065)

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immune reconstitution inflammatory syndrome (IRIS)

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basics

• IRIS occurs when increased immune function leads to enhanced immune activity against pathogens. This may lead to clinical deterioration in various infections, prior to eventual improvement.
• Different types of IRIS:
  • Paradoxical IRIS: deterioration of a previously recognized infection.
  • Unmasking IRIS: initial presentation of a previously subclinical infection.
• IRIS may also lead to various autoimmune responses, which may have previously been muted by HIV (e.g., sarcoidosis).
• Clinical presentation varies widely, depending on the cause (e.g., IRIS due to tuberculosis may manifest with worsening pulmonary infiltrates, fever, and expanding lymphadenopathy).

epidemiology

• IRIS usually occurs within 1-3 months after starting antiretroviral therapy (but some cases may present several months after starting therapy).
• Risk factors:
  • Low pre-treatment CD4 count (<50-100/uL).
  • High pre-treatment viral load.
  • Antiretroviral therapy initiated in the context of a known opportunistic infection.

causes of IRIS

• Infection: virtually any infection can cause IRIS, but the risk is greatest with the following:
  • Mycobacterial infections:
    • Mycobacterium avium complex (MAC) is the most common cause of IRIS, affecting ~3% of patients started on antiretroviral therapy. (26149556)
    • M. tuberculosis is also possible, but this is more pathogenic so that it's somewhat less likely to be asymptomatic prior to initiation of antiretroviral therapy.
  • Fungal infections (e.g., PJP, cryptococcal meningitis, endemic fungi).
  • Viral infections (e.g., CMV retinitis, JC virus causing PML).
• Noninfectious conditions:
  • Sarcoidosis (sarcoid-related IRIS is reported up to three years after starting antiretroviral therapy).
  • Malignancy (e.g., Kaposi sarcoma).
  • Autoimmune conditions.

diagnosis

• Diagnosis of IRIS should include the following elements:
  • Low pre-treatment CD4 count (e.g., <100/uL).
  • Robust response to antiretroviral therapy (e.g., rising CD4 count, falling viral load).
  • Adherence to antiretroviral therapy.
• Diagnosis of IRIS involves exclusion of other etiologies, including:
  • Infection.
  • Malignancy.
  • Drug toxicity.
• If available, antigen levels may be helpful (e.g., a falling cryptococcal serum antigen supports the diagnosis of IRIS, rather than uncontrolled infection).
• Tissue diagnosis may be needed in some cases.

management

• Antiretroviral therapy should generally be continued.
• Antimicrobial therapy against causative pathogen is usually indicated.
• Supportive care including antipyretics may be helpful.
• Steroid may be required if severe inflammation is causing end-organ damage.
  • IRIS is generally well tolerated, but one notable exception is neurologic infections. Thus, steroid could have a greater role for IRIS causing neurologic dysfunction or elevated intracranial pressure.

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transplantation

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Transplantation predisposes patients to a variety of infectious and noninfectious complications. These may depend on the nature of the transplant, the immunosuppression regimen, and the timing since transplantation. Typical patterns of complications are as follows:

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complications following solid organ transplantation

<1 month

• Drug-resistant species, including:
  • MRSA.
  • VRE.
  • Candida species (non-albicans).
  • Pseudomonas spp.
• Hospital-acquired infections:
  • Aspiration.
  • Catheter infection.
  • Surgical site infection.
  • Anastomotic leaks and ischemia.
  • C. difficile colitis.
• Donor-derived infections:
  • CMV.
  • HSV.
  • HIV (rare).
  • Rabies (rare).
  • Zika virus (rare).
• Recipient-derived infections (colonization):
  • Aspergillus.
  • Pseudomonas spp.

1-6 months

• Without prophylaxis:
  • Pneumocystis jirovecii pneumonia (PJP).
  • Herpesviruses (e.g., VZV, HSV-1, HSV-2, HSV-6, CMV, EBV).
  • Listeria monocytogenes.
  • Nocardia spp.
  • Toxoplasma gondii.
  • Strongyloides spp.
  • Adenovirus.
  • Influenza.
  • C. difficile.
  • Aspergillus spp.
• With prophylaxis (antiviral, antifungal, PJP):
  • Respiratory viruses (influenza, adenovirus, RSV).
  • Cryptococcus neoformans.
  • Mycobacterial infections (e.g., TB).

>6 months

• Community acquired:
  • Streptococcus pneumoniae
  • Nocardia spp.
  • Rhodococcus spp.
  • Mold infections (Aspergillus spp., Mucorales spp.).
  • Endemic fungi.
  • Respiratory viruses.
• Late diseases with immunosuppression:
  • BK virus.
  • CMV.
  • Herpesviruses (e.g., VZV, HSV-1, HSV-2, HSV-6, CMV, EBV).
  • JC polyomavirus.
  • PTLD (post-transplant lymphoproliferative disorder).
  • Squamous cell carcinoma of the skin.

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complications after hematopoietic stem cell transplantation

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neutropenia

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risk of opportunistic infection

• Risk relates to the combination of the severity and duration of neutropenia. (ERS handbook 3rd ed.)
  • Low risk: Neutrophil count 500-1,000/uL.
  • High risk:
    • Neutrophil count <500/uL for >7 days.
    • Neutrophil count <100/uL for <7 days.
  • Very high risk: Neutrophil count <100/uL for >14 days.
• Risk of invasive fungal infection, in particular, increases with prolonged durations of neutropenia (e.g. >~10 days).

pathogens to consider

• Bacteria:
  • Pseudomonas aeruginosa.
  • Stenotrophomonas maltophilia.
  • Enterobacteriaceae.
  • Streptococcus mitis.
  • Staphylococcus aureus.
• Nocardia spp.
• Fungi:
  • Aspergillus and other hyaline molds (Scedosporium, Fusarium).
  • Mucorales spp.
  • Endemic fungi. (32561442)
  • Yeast-like fungi (Trichosporon).

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lymphopenia

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definition & significance of lymphopenia

• A normal absolute lymphocyte count is 1,000 – 4,800/uL (of which ~70% are T-cells). (24591476)
• Among patients with HIV, a lymphocyte count <800/uL is 100% specific for having a CD4 count <200/uL. (24963572)
• Acute lymphopenia commonly occurs within the context of acute illness. However, chronic lymphopenia is more significant in terms of indicating clinically significant immunosuppression.
• Chronic severe lymphopenia (<500/uL) may predispose to opportunistic infections (e.g., Pneumocystis, systemic cytomegalovirus). (24591476)

causes of lymphopenia

• Infections or acute physiologic stress often causes acute lymphopenia:
  • Bacteria (including M. tuberculosis).
  • Viral infection (including influenza, COVID, hepatitis viruses).
  • Fungi (including Histoplasma).
  • Parasites (including malaria).
  • Surgery.
• Primary immunodeficiency:
  • CVID (common variable immunodeficiency).
  • IgA deficiency.
• Acquired immunodeficiency:
  • HIV.
  • Idiopathic CD4+ lymphocytopenia.
• Iatrogenic:
  • Steroid.
  • Chemotherapy (e.g. fludarabine, cladribine).
  • Radiation.
  • Methotrexate, azathioprine.
  • Monoclonal antibody therapy (e.g., rituximab).
• Autoimmune diseases:
  • Rheumatoid arthritis.
  • Lupus.
  • Inflammatory bowel disease.
  • Sarcoidosis.
• Malignancy:
  • Lymphoproliferative disorders, including lymphoma.
  • Solid organ malignancies.
• Other:
  • Renal failure, cardiac failure.
  • Aplastic anemia.
  • Cushing disease.
  • Heavy alcohol use.
  • Malnutrition.
  • Protein-losing enteropathy. (24963572, 24591476)

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hypogammaglobulinemia

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causes of hypogammaglobulinemia:

• CVID (common variable immunodeficiency).
• Multiple myeloma.
• Biologics that target CD19/20 (e.g., rituximab).

pathogens to consider include:

• Respiratory viruses (influenza, RSV, human metapneumovirus, parainfluenza, adenovirus, COVID).
• Encapsulated bacteria (Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, Staphylococcus aureus, Capnocytophaga, Pasteurella multocida).
• CMV.
• Pneumocystis. (32561442)

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pulmonary complications related to selected immunosuppressive medications

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opportunistic pneumonia due to corticosteroid 

Steroid may increase the risk of a variety of infections. The following infections may be of particular interest:

• Pneumocystis (usually seen with >15-20 mg/day prednisone-equivalents for >1-2 months; risk varies depending on underlying condition).
• Fungal infections:
  • Endemic mycoses.
  • Cryptococcus neoformans infection.
  • Invasive aspergillosis or mucormycosis (usually seen following only very high steroid doses).
• Tuberculosis (reactivation of latent infection).
• Nocardia infection.
• Disseminated strongyloidiasis.
• Viruses (CMV, VZV, HSV).

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lung disease related to TNF-inhibitor therapy

opportunistic infections

• Fungal infection:
  • Endemic fungi.
  • Aspergillus.
  • Pneumocystis.
• Mycobacteria:
  • Tuberculosis.
    • Infliximab and adalimumab may be higher risk than etanercept, possibly due to their induction of complement-mediated cell lysis. (28185620)
    • Tuberculosis reactivation often occurs relatively soon after initiation of therapy (e.g., median of three months after starting treatment). (28185620)
    • Extrapulmonary and disseminated tuberculosis is common.
  • NTM (nontuberculous mycobacteria).
• Varicella zoster virus.
• Nocardia. (32561442)

immune-related adverse events

• Vasculitis.
• Lupus-like events.
• Sarcoidosis.
• Interstitial lung disease (discussed below).

anti-TNF induced interstitial lung disease

• Epidemiology:
  • Prevalence may be ~0.5-3 %. (30409366)
  • Etanercept is most frequently implicated, followed by infliximab and adalimumab. (30409366)
  • Usually begins ~2-6 months after initiation of therapy. (30409366, 36865931)
  • Most frequently associated with underlying rheumatoid arthritis. (30409366)
• Symptoms:
  • Dyspnea (86%), cough (38%). (30409366)
  • Constitutional symptoms: fever (44%), malaise.
• Radiology:
  • Various patterns may be seen, including NSIP, UIP, and OP (organizing pneumonia). (30409366)
  • Specific findings include: (30409366)
    • Ground-glass opacities (83%).
    • Honeycombing (22%).
• Laboratory studies:
  • anti-TNF may stimulate the induction of multiple, unrelated autoantibodies. These may lead to diagnostic confusion by suggesting connective tissue-related ILD. (30409366)
• Management:
  • Discontinuation of TNF-inhibitor is the cornerstone of management.
  • Steroid may be utilized.

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T-cell depletion (anti-thymocyte globulin, alemtuzumab)

pathogens include:

• Pneumocystis.
• Streptococcus pneumoniae.
• Mycobacteria (including M. tuberculosis, M. avium intracellulare).
• Mold (including Aspergillus and other hyaline molds, Mucorales spp.).
• VZV, HSV, CMV.
• Histoplasma capsulatum, Coccidioides.
• Toxoplasma gondii.
• Cryptococcus neoformans.
• Nocardia.
• Legionella.
• Strongyloides.

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B-cell depletion (e.g., rituximab)

infections

• COVID-19.
• Bacterial pneumonia may be increased (which may be more likely in patients with lower IgG levels).
• Pneumocystis pneumonia might be roughly twice as likely among patients treated with rituximab. This is difficult to understand fully because patients are often immunosuppressed for additional reasons, and because a definitive diagnosis of invasive Pneumocystis is not always reached. (24590034) 

rituximab-induced ILD

• This is rare (incidence of ~0.02%). It is most common in older men, about 30 days after their last dose. (30131832) 
• Imaging may show nonspecific pulmonary infiltrates.
• Bronchoscopy usually shows lymphocytosis, but lung pathology is variable. (30131832) 

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antimetabolites 

commonly used antimetabolites:

• Mycophenolate mofetil.
• Azathioprine.
• 6-mercaptopurine.
• Fludarabine.

pathogens to consider:

• CMV.
• Varicella.
• Respiratory viruses (if B-cell impairment).
• Legionella.
• Nocardia.
• Aspergillus and other hyaline molds.
• Mucorales spp.
• Endemic fungi.
• Pneumocystis post-fludarabine. (32561442)

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tyrosine kinase inhibitors (e.g., ibrutinib, dasatinib) 

noninfectious complications:

• Pneumonitis may occur, usually within 1-4 months of ibrutinib initiation. (34723761)
• Pleural effusion (especially dasatinib, which may cause pleural effusion in ~20% of patients). (ERS handbook 3rd ed.)
• Precapillary pulmonary hypertension.

infectious complications:

• Fungal infections:
  • Pneumocystis.
  • Mold.
  • Cryptococcosis.
• CMV. (32561442)
• ⚠️ Ibrutinib may cause persistent reduction in B- and T-lymphocytes for possibly up to ~1-2 years after cessation (although this remains poorly understood). (34723761)

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other associations 

• Natalizumab: Cryptococcus.
• Vedolizumab: Mycobacterium tuberculosis.
• Eculizumab: Pseudomonas, mold.
• Bortezomib: varicella-zoster virus. (32561442)

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common variable immunodeficiency (CVID)

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basics

• CVID is also known as acquired hypogammaglobulinemia. (Murray 2022) It is a heterogeneous disorder characterized primarily by immunoglobulin deficiency, which is often diagnosed in adulthood. 
• CVID involves a defect in the terminal differentiation of B-cells into plasma cells. This results in a deficiency of plasma cells and immunoglobulin.
• Aside from causing a deficiency of immunoglobulins, CVID may cause autoimmune manifestations.

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epidemiology of CVID

• CVID is the most common non-acquired immune deficiency disorder (although it's still rare, affecting roughly ~1/50,000 people).
• Onset is most frequent between 20-40 years old (but may occur at any age).
• Most cases arise de novo, but 5-25% are familial. (Teneback 2022)

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manifestations of CVID

opportunistic infections

• Patients may develop a broad range of opportunistic infections, including sinusitis and pneumonia.
• Common pathogens include:
  • Encapsulated bacteria are very common (e.g., Haemophilus influenzae, Streptococcus pneumoniae).
  • Atypical bacteria (e.g., Mycoplasma).
  • Gram-negative rods. (Murray 2022)
  • Some fungal infections (e.g., Cryptococcus).

pulmonary manifestations

• Bronchiectasis commonly evolves over time.
  • Usually most severe involvement of the middle and lower lobes.
• Asthma.
• Organizing pneumonia.
• Granulomatous and lymphocytic interstitial lung disease (GLILD; discussed further below).
• LIP (lymphocytic interstitial pneumonia).
• Follicular bronchiolitis.
• Primary pulmonary lymphoma may occur.

nonpulmonary manifestations:

• Gastrointestinal tract: 
  • Inflammatory bowel disease.
  • Malabsorption (higher incidence of bacterial overgrowth).
  • Malignancy.
  • Celiac disease.
  • Infections (including Giardia, Norovirus, H. pylori).
• Liver/spleen:
  • Granulomas.
  • Cholestasis (possibly related to nodular hyperplasia).
  • Cirrhosis, portal hypertension.
  • Splenomegaly and hypersplenism.
• Hematological:
  • ITP (immune thrombocytopenia).
  • Autoimmune hemolytic anemia.
  • Autoimmune neutropenia.
  • Pernicious anemia.
• Autoimmune conditions
  • Rheumatoid arthritis.
  • Lupus.
  • Autoimmune endocrinopathies (e.g., thyroiditis).
  • Vitiligo, alopecia.
  • Celiac disease, inflammatory bowel disease.
• Malignancy:
  • Non-Hodgkin lymphoma.
  • BALT- and MALT-related disorders.
  • Gastric, cervical, bladder, and breast cancer. (31128118)

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diagnosis of CVID

laboratory studies

• IgG levels:
  • The normal adult level of IgG is 600-1600 mg/dL.
  • Most patients with CVID have IgG levels <250-450 mg/dL.
  • During active infection, total IgG levels may increase. This may cause some patients to have a normal total IgG level, with only an IgG subclass deficiency.
• IgM, IgA levels:
  • Patients can progress to be deficient in all types of immunoglobulins (including IgA and IgM).
  • CVID diagnostic criteria include reduction of IgA or IgM (discussed further below).
• Autoimmune cytopenias may occur (e.g., immune thrombocytopenia).
• ACE levels may be elevated (remember that ACE levels are a biomarker of granuloma formation).

histologic findings

• Noncaseating granulomas are frequently found in virtually any organ (e.g., lungs, spleen, liver, skin, bone marrow, lymph nodes). (Murray 2022) This may lead to misdiagnosis as sarcoidosis.

differential diagnosis: other causes of hypogammaglobulinemia

• Other primary immunodeficiency:
  • Good syndrome (thymoma in the context of hypogammaglobulinemia).
    • Patients usually present in their 40s-50s.
    • Pulmonary infection is the most common manifestation, often eventually leading to bronchiectasis. (33447285)
    • Treatment involves thymectomy and immunoglobulin supplementation.
  • X-linked agammaglobulinemia.
  • X-linked lymphoproliferative disease.
  • Hyper-IgM syndrome.
• Protein loss:
  • Protein losing enteropathy.
  • Nephrotic syndrome.
• Medication-induced hypogammaglobulinemia:
  • Steroid (e.g., prednisone 20 mg/day for >2 weeks, or long-term low-dose steroid). (31128118)
  • Immunosuppressives: Azathioprine, cyclosporine, mycophenolate, cytotoxic agents (e.g., cyclophosphamide), rituximab and other B-cell suppressive agents.
  • Other medications:
    • Captopril.
    • Antimalarial medications.
    • Carbamazepine.
    • Levetiracetam.
    • Phenytoin.
    • NSAIDs.
    • Oxcarbazepine.
    • Penicillamine.
    • Phenytoin.
    • Sulfasalazine.
• Other causes of hypogammaglobulinemia:
  • B-cell lymphomas.
  • Paraproteinemias: myeloma, Waldenstrom macroglobulinemia.
  • Bone marrow failure.
  • Transient hypogammaglobulinemia secondary to infection.

European Society of Immunodeficiency criteria for probable CVID:

• At least one of the following:
  • Increased susceptibility to infection.
  • Autoimmune manifestations.
  • Granulomatous disease.
  • Unexplained polyclonal lymphoproliferation.
  • Affected family member with antibody deficiency.
• Marked reduction of IgG (at least two standard deviations below normal, measured twice at least 3 weeks apart).
• Associated with low IgA and/or low IgM levels.
• At least one of the following:
  • Poor antibody response to vaccines (i.e., absence of protective concentrations despite vaccination).
  • Absent isohemagglutinins.
  • Low number of switched memory B-cells (<70% of age-related normal value).
• Secondary causes of hypogammaglobulinemia have been excluded.
• Diagnosis established after 4th year of life.
• No evidence of profound T-cell deficiency.

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treatment of CVID

intravenous immunoglobulin (IVIG)

• Administration of IVIG is essential to prevent and manage complications.
• Patients may receive maintenance IVIG doses monthly.
• Trough IVIG levels:
  • Initially a trough level of IgG >750 mg/dL may be reasonable.
  • For patients receiving immunosuppression (e.g., for GLILD), higher trough levels of immunoglobulin should be targeted (e.g., IgG level >1,000 mg/dL). (31128118)

management of infection

• There should be a low threshold to provide coverage for infection, especially encapsulated bacteria.
• Longer durations of therapy may be needed for acute infections. (Teneback 2022)

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GLILD (granulomatous and lymphocytic interstitial lung disease)

basics

• GLILD occurs in ~20% of patients with CVID.
• GLILD is a multisystemic lymphoproliferative and granulomatous disease, with granulomas potentially affecting any organ (including bone marrow, liver, spleen, and lymph nodes). (Murray 2022) Within the lung, GLILD causes interstitial lymphocytic infiltration, granulomatous inflammation, and organizing pneumonia. (Fishman 2023) 

epidemiology: among patients with CVID, GLILD is associated with:

• Splenomegaly or hepatosplenomegaly.
• Immune thrombocytopenic purpura or autoimmune hemolytic anemia.
• Low serum IgA level. (30044751)

clinical presentation

• Dyspnea and chronic cough are the most common symptoms.
• Hepatosplenomegaly.

radiology

• Parenchymal findings may include the following, with lower lobe predominance:
  • Small and large nodules are the most common finding. A peribronchial pattern may occur that mimics sarcoidosis. (ERS handbook 3rd ed.) However, nodules can also have a random or centrilobular pattern, which can help distinguish CVID from sarcoidosis. (33447267)
  • Multifocal ground-glass opacities or pulmonary consolidation.
  • Smooth interlobular septal thickening.
  • (Eventually, fibrosis may develop.)
• Thoracic lymphadenopathy is commonly seen (due to granulomatous inflammation).
• Hepatosplenomegaly or splenomegaly may also be seen.
• Bronchiectasis may be seen (although this probably relates to the underlying combined variable immunodeficiency, rather than GLILD).

diagnosis

• Bronchoalveolar lavage usually shows lymphocytosis without evidence of infection. (30732702)
• Surgical lung biopsy is generally needed:
  • (a) To differentiate this from lymphoma or other lymphoproliferative disorders.
  • (b) To render a definitive diagnosis (which is needed to initiate multimodal immunomodulator therapy).
• An alternative approach to tissue biopsy which may sometimes be considered is a lymph node excisional biopsy (especially if PET-CT scan suggests the presence of a diffuse inflammatory process). (33447267)

treatment

• Patients must also be treated simultaneously for CVID, as described above. In particular, IVIG should be initiated prior to immunosuppressive therapies. (33447267)
• Anti-CD20 monoclonal therapy (e.g., rituximab) may be a very helpful therapy, for a few reasons:
  • (1) B-cell hyperplasia is a major driving factor in GLILD. (33447267)
  • (2) B-cell function is already impaired, so ablation of B-cells may not have a major immunosuppressive effect on these patients.
• In more severe cases, combination therapy involving rituximab plus azathioprine or mycophenolate may be effective. (Fishman 2023) 
• GLILD often responds poorly to steroid or subsequently relapses after steroid is weaned.

prognosis

• Progressive respiratory dysfunction develops in ~25% of patients. (ERS handbook 3rd ed.)

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chronic granulomatous disease (CGD)

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basics

• NADPH oxidase deficiency causes a reduction in peroxide production. This impairs the ability of neutrophils to generate reactive oxygen species, interfering with their function, as well as causing inflammatory dysregulation (even in the absence of infection). (33036114)

epidemiology

• ~75% of patients are men (CGD is frequently occurs as an X-linked, recessive disorder).
• CGD usually manifests in childhood, but more mild cases may present in adulthood.

patients have increased susceptibility to catalase-positive bacteria and fungi, especially:

• Most commonly implicated organisms in pneumonia, in descending order: (31259635)
  • Aspergillus spp. (41%).
  • Staphylococcus aureus (11%).
  • B. cepacia complex (7%).
  • Nocardia (6%).
  • Serratia (4%).
  • Klebsiella (3%).
  • Pseudomonas (3%).
  • Mycobacteria (3%).
• Aspergillus and other molds:
  • Invasive fungal infection is the most common cause of death. Among all primary immunodeficiencies, CGD has the highest rate of invasive fungal infections with about a third of patients affected. (34872678)
  • Fungal pneumonia may manifest as an indolent progressive pneumonia, without cavitation or fever (due to altered immune responses). (33036114)

clinical presentations include:

• Most common sites of infection: (31259635)
  • Pneumonia (~80% of patients in a large series).
    • “Mulch pneumonitis” refers to intense exposure to organic dust that causes fulminant fungal pneumonia, usually with Aspergillus fumigatus or Aspergillus nidulans. (Murray 2022) Fungal exposure may result from gardening or yard work (e.g., mulching, raking leaves, mowing lawns). (29714104) The term “pneumonitis” may be a bit misleading, since these patients have invasive infection. 
  • Soft tissue abscess (~70%).
  • Suppurative adenitis (~50%)
  • Osteomyelitis (~25%)
  • Bacteremia (~20%).
• Patients may fail to show usual signs of infection (e.g., fever). (25644916)
• Failure to clear infections may also cause autoimmune manifestations:
  • Sterile granulomas may occur in the skin, gastrointestinal, or genitourinary tracts.
  • A noninfectious, granulomatous interstitial lung disease can occur (which can mimic sarcoidosis). (Murray 2022)
  • An inflammatory colitis is common (which mimics Crohn disease).

radiology

• Acute infections may have a variety of radiologic patterns (depending on the pathogen).
• Striking lymphadenopathy can occur.
• Eventually, bronchiectasis may develop.

laboratory studies

• The preferred test is dihydrorhodamine (DHR) test, which uses flow cytometry to detect the reduction of dihydrorhodamine to its fluorescent form, thereby functionally testing for phagocyte NADPH oxidase function. (Murray 2022)
• Positive results may be confirmed by genotyping (with abnormalities potentially occurring in genes involved in NADPH oxidase including: CYBB, NCF1, NCF2, NCF4, CYBA, or CYBC1). (34872678) Different genetic abnormalities may correlate with varying disease severity.

treatment

• Any acute infections should be managed.
  • In patients with pneumonia, it may be reasonable to include empiric antifungal therapy as a component of initial treatment. (34872678)
  • For patients with mulch pneumonitis (aggressive fungal pneumonia due to intense exposure), steroid might be helpful alongside antifungal therapy. (29714104)
• Patients may benefit from chronic prophylactic antibiotics (e.g., trimethoprim-sulfamethoxazole and itraconazole).
• For recurrent, life-threatening infection bone marrow transplantation can be a consideration.

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hyper-immunoglobulin E syndrome (HIES)

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basics

• This is also known as Job syndrome.
• HIES is due to mutations in the STAT-3 gene, which has a variety of downstream consequences:
  • Absence of anti-inflammatory IL-10 may cause dysregulated inflammatory responses.
  • Absence of IL-6 causes a deficiency of CD4+ Th17 cells – leading to inadequate defense against extracellular bacteria and fungi. (Murray 2022)

epidemiology

• Rare.
• Most cases are sporadic or autosomal dominant with incomplete penetrance.

clinical manifestations

• Recurrent pyogenic infections (including skin, sinusitis, pneumonia, and bronchiectasis).
  • Common pathogens include Staph. aureus, Streptococcus pneumoniae, Haemophilus influenzae.
  • Pneumatocele formation frequently complicates recurrent staphylococcal pneumonia. Pneumatoceles may become superinfected with Pseudomonas or Aspergillus, causing severe invasive infections. Rupture of pneumatoceles may cause pneumothorax.
  • Pneumonia may have limited clinical symptoms, due to a pathologically low level of inflammation. (Murray 2022)
  • Bronchiectasis may occur.
• Eczema (a diffuse eczematous rash may occur).
• Most forms of HIES additionally cause skeletal and connective tissue abnormalities:
  • Patients may have scoliosis, recurrent fractures due to osteopenia, and hyperextensible joints.
  • Facial appearance may show frontal bossing, a broad nose, and a prominent lower lip.

laboratory studies

• IgE is usually markedly elevated (e.g., >2000 IU/ml). However, IgE levels may decrease over time, so normal IgE levels don't exclude the diagnosis. (Murray 2022)
• Peripheral eosinophilia is typical.

treatment

• Infections should be aggressively treated (including especially coverage for Staphylococcus).
• Prophylactic antibiotics to prevent Staphylococcus infections may be helpful (e.g., trimethoprim-sulfamethoxazole).
• Some forms of the disease may benefit from stem cell transplantation.

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bacterial gram-stain morphology

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Gram-staining morphology cannot definitively identify the bacterial species, but it may provide some useful clues. Below are lists of the most common types of bacteria that cause various morphologies on Gram-staining. 

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gram-positive species

gram-positive cocci (GPCs)

• Clusters:
  • Staphylococcus aureus.
  • Coagulase-negative Staphylococcus (e.g., Staphylococcus epidermidis).
  • (Less likely: Micrococcus, Pediococcus, Aerococcus, Stomatococcus.)
• Pairs:
  • Streptococcus pneumoniae (although this may also cause short chains).
• Pairs / chains:
  • Streptococci:
    • Streptococcus pyogenes (group A Streptococcus).
    • Streptococcus agalactiae (group B Streptococcus).
    • Groups C, F, G streptococci.
    • Streptococcus viridans.
    • Streptococcus pneumoniae.
  • Enterococci.
  • Anaerobes:
    • More likely: Peptostreptococcus, Peptococcus.
    • Rarely: Leuconostoc, Abiotrophia, Granulicatella, Gemella, Finegoldia.

gram-positive bacilli (rods)

• Small (e.g., coccobacilli) or medium size:
  • Listeria morphology is variable (but suggested by small gram-positive coccobacilli).
  • Coryneform (“diphtheroid”) – pleomorphic or club-shaped and arranged in parallel formations that may resemble Chinese letters:
    • Corynebacterium spp. (including C. jeikeium, C. diphtheriae).
    • Cutibacterium (formerly Propionibacterium).
    • Listeria.
  • Gardnerella.
  • Lactobacillus.
  • Bifidobacterium.
  • Eubacterium.
  • Rhodococcus (weakly acid fast).
• Large, boxcar shaped:
  • Clostridium spp. (anaerobic).
  • Bacillus anthrax (aerobic).
• Branching:
  • Nocardia spp. (aerobic).
  • Actinomyces spp. (anaerobic).
  • Streptomyces and Cutibacterium may also be possible.
  • (See: Nocardia vs. Actinomyces 📖)

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gram-negative species

gram-negative cocci

• Neisseria spp. are typically in pairs (diplococci):
  • Neisseria meningitidis.
  • Neisseria gonorrhoeae.
• Moraxella catarrhalis.
• Acinetobacter spp. may have this appearance.
• Anaerobic Veillonella spp.

gram-negative coccobacilli

• Haemophilus influenzae.
• Moraxella catarrhalis.
• Bordetella pertussis.
• Yersinia pestis.
• Tularemia.
• Ehrlichiosis.
• Anaplasmosis.
• Pasteurella spp.
• Brucella spp.

gram-negative bacilli (rods)

• Lactose fermenting:
  • Oxidase positive:
    • Aeromonas.
    • Pasteurella multocida.
    • Capnocytophaga canimorsus.
    • Vibrio.
  • Oxidase negative:
    • E. coli.
    • Klebsiella.
    • Enterobacter.
    • Citrobacter.
• Non-lactose fermenting:
  • Oxidase positive:
    • Pseudomonas.
    • Moraxella.
  • Oxidase negative:
    • Proteus.
    • Serratia.
    • Acinetobacter (although occasionally this may also appear as gram positive).
    • Stenotrophomonas.
    • Morganella.
    • Salmonella.
    • Shigella
• Anaerobes include:
  • Bacteroides.
  • Prevotella.
  • Porphyromonas.
  • Fusobacterium.

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fungal morphologies

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blastomycosis: broad-based budding yeasts (10-15 uM)

• Most suggestive of blastomycosis, with features:
  • Size 8-15 uM.
  • Thick refractile cell walls.
  • May show a single, broad-based bud.
• May be confused with: endospores of Coccidioides, Candida, Histoplasma, Cryptococcus, Aspergillus conidia.
  • Endospores of Coccidioides may resemble blastomycosis, but endospores of Coccidioides don't display broad-based budding.
  • Blastomyces may sometimes be as small as Cryptococcus neoformans (4-10 uM). However, Cryptococcus may be differentiated based on narrow-based budding and prominent mucoid capsule.

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cryptococcus: narrow-based budding yeasts (~4-10 uM) 

• Features suggestive of Cryptococcus:
  • Prominent mucoid capsule that stains positive on mucicarmine staining.
  • Cryptococcus produces melanin that can be seen on Fontana-Masson staining. (26540422)
  • Narrow-based budding.
• May be confused with: Candida spp., Histoplasma spp.

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histoplasma: small yeasts (2-4 uM) 

• Histoplasma capsulatum: 📖
  • Small (2-4 uM), ovoid yeast with narrow-based budding.
  • Yeast are predominantly intracellular. Finding yeast within macrophages help point towards histoplasmosis (rather than Candida infection or Pneumocystis pneumonia). (28797485)
  • Because yeasts are initially ingested by macrophages, they appear to be clustered. (21482725)
• May be confused with:
  • Small variant of Blastomyces dermatitidis.
  • Capsule-deficient Cryptococcus.
  • Endospores of Coccidioides.
  • Pneumocystis jirovecii.
  • Penicillium marneffei
  • Candida glabrata.

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coccidioides: spherules with endospores (10-100 uM)

• Most suggestive of Coccidioidomycosis.
• May be confused with Blastomyces, Histoplasma, Candida, PJP and other yeasts when no spherule is present.

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candida: small yeasts (3-5 uM) with pseudohyphae & hyphae

• Most consistent with Candida infection.
• May be confused with Aspergillus spp. and other hyaline fungi.

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nonpigmented (hyaline), septate hyphae with acute angle-branching

• Non-pigmented (hyaline), septate hyphae may be seen in:
  • Aspergillus spp.
  • Fusarium spp.
  • Scedosporium spp.
  • Trichoderma spp.
  • Paecilomyces spp.
  • (Mucorales genera may sometimes have this morphology.)

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nonpigmented (hyaline), pauciseptate ribbon-like hyphae with right-angle branching

• Most consistent with Mucorales genera.

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pigmented irregular hyphae and yeast-like structures with septations

• Most consistent with dematiaceous fungi including: Madurella spp., Fonsecaea spp., Cladophialophora spp., Exophiala spp., Curvularia spp., Bipolaris spp.

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thin-walled spheres (2-5 uM) with intracystic foci

• Most consistent with Pneumocystis.
• When occurring outside the lung (which is rare), may be confused with Histoplasma.

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small oval-shaped yeasts (2-5 uM) with transverse septum

• Penicillium marneffei.

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variable size yeasts (4-60 uM) with multiple buds surrounding the parent cell

• Diagnostic of Paracoccidioides brasiliensis.
• May be confused with: Sporothrix or Cryptococcus (if only one or two buds are present).

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asteroid bodies (star-like eosinophilic material surrounding yeasts)

• Asteroid bodies (star-like eosinophilic material surrounding yeasts) are usually found in sporotrichosis.
• May be confused with: Candida glabrata, Histoplasma, Leishmania, sarcoidosis.

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dimorphic fungi

Dimorphic fungi refer to organisms which grow as yeasts within tissue, but as molds outside of the body. This is a characteristic seen in most endemic mycoses (e.g., histoplasmosis, blastomycosis). If an organism appears as yeast on histopathology and then grows as a mold within the laboratory, this suggests the presence of a dimorphic fungus.

Dimorphic fungi include: (32433841)

• Histoplasma.
• Blastomyces.
• Sporothrix schenckii.
• Coccidioides spp.
• Paracoccidioides brasiliensis.
• Penicillium marneffei.

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questions & discussion

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