Fungal Infections in Immunocompromised Hosts
The type and the risk of fungal infection depend on the immune defect (neutropenia, T cell dysfunction, phagocyte disorders, barrier breach), the duration of exposure, the epidemiology of the unit, and the use of prophylaxis.
Recognising the host group allows prediction of the likely pathogens, selection of a prophylaxis strategy, interpretation of tests, and rational empirical and pre-emptive treatment.
The commonest pathogens in these hosts are Candida, Aspergillus, Cryptococcus, Pneumocystis jirovecii, Mucorales, Fusarium, Scedosporium, and the endemic dimorphic fungi.
| Defect | Main pathogens | Notes |
|---|---|---|
| Prolonged neutropenia (absolute neutrophil count below 0.5 times 10 to the 9 per litre for more than 10 days) | Aspergillus, Candida (including non albicans species), Mucorales, Fusarium, Scedosporium, Trichosporon, Saprochaete | Acute myeloid leukaemia induction and relapse, myelodysplastic syndrome, and allogeneic stem cell transplant |
| T cell and macrophage defects | Pneumocystis, Cryptococcus, Histoplasma, Coccidioides, Talaromyces, Candida (mucosal), Aspergillus | HIV, transplant, corticosteroids, purine analogues, alemtuzumab, and calcineurin inhibitors |
| Corticosteroids (prednisone 20 mg or more daily for 3 weeks or more) | Pneumocystis, Aspergillus, Cryptococcus, Mucorales, endemic fungi | Dose and duration determine risk |
| Phagocyte disorders | Aspergillus (chronic granulomatous disease, often Aspergillus nidulans), Candida | Neutrophil function defects, leucocyte adhesion deficiency |
| Primary immunodeficiency | Chronic mucocutaneous candidiasis (STAT1 gain of function, AIRE, IL17 pathway defects), Aspergillus and Candida (hyper IgE syndrome from STAT3), invasive infection with CARD9 deficiency (Candida, dermatophytes, phaeohyphomycosis), endemic mycoses and Cryptococcus (IFNGR1, IL12RB1, GATA2) | Often presenting in early life |
| Complement and barrier defects | Candida from catheters, burns, and gut breach | Intensive care, parenteral nutrition, surgery |
| Diabetes, cirrhosis, kidney disease | Mucorales, Candida, Cryptococcus, Aspergillus | Ketoacidosis and iron overload |
| Biologic and targeted agents | Tumour necrosis factor inhibitors (histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis), ibrutinib (aspergillosis, including cerebral, and cryptococcosis), idelalisib (pneumocystis), ruxolitinib (cryptococcosis and others), rituximab, CAR T cell therapy, and venetoclax | Risk depends on the agent and its combination with corticosteroids |
| Premature neonates | Candida (invasive candidiasis, with Candida albicans and Candida parapsilosis), Malassezia with lipid infusions | Low birth weight, central catheters, and broad spectrum antibacterials |
Haematological malignancy and chemotherapy
Acute myeloid leukaemia and myelodysplastic syndrome during induction and salvage have the highest risk of invasive aspergillosis and candidiasis. Acute lymphoblastic leukaemia carries a lower risk of mould disease but a risk of pneumocystis pneumonia. Lymphoma, chronic lymphocytic leukaemia, and myeloma are at risk from purine analogues, alemtuzumab, bendamustine, corticosteroids, and Bruton tyrosine kinase inhibitors.
Haematopoietic stem cell transplant
| Phase | Timing | Defect | Typical infections |
|---|---|---|---|
| Pre-engraftment | Day 0 to about day 30 | Neutropenia, mucositis, catheters | Candida (bloodstream), Aspergillus, Mucorales, Fusarium |
| Early post engraftment | Day 30 to 100 | Acute graft versus host disease, corticosteroids, impaired cellular immunity | Aspergillus (the peak of invasive mould disease in this period), Pneumocystis, Candida, Mucorales |
| Late | After day 100 | Chronic graft versus host disease, immunosuppression, and asplenia | Aspergillus, Pneumocystis, Mucorales, endemic fungi |
Risk factors for invasive mould infection are allogeneic and unrelated donor transplant, cord blood and haploidentical transplant, acute and chronic graft versus host disease, high dose corticosteroids, and prior mould infection.
Solid organ transplant
| Organ | Main fungal risks |
|---|---|
| Lung and heart lung | Aspergillus tracheobronchitis and anastomotic infection (the highest rate of invasive aspergillosis), Candida, Scedosporium, and Mucorales; fungal colonisation of the airway before transplant |
| Liver | Candida (intra-abdominal, bloodstream), Aspergillus (high mortality), and Cryptococcus; risk increases with retransplant, renal replacement, and operation time |
| Kidney | Candida (urinary tract), Cryptococcus, Pneumocystis, and endemic mycoses |
| Heart | Aspergillus and Candida |
| Pancreas and small bowel | Candida, with intra-abdominal infection |
| Timing | The first month (surgical and nosocomial infections: Candida), 1 to 6 months (opportunistic: Pneumocystis, Aspergillus, Cryptococcus), and beyond 6 months (community acquired, endemic, and late Aspergillus and Cryptococcus) |
HIV
| CD4 count (cells per microlitre) | Fungal infections |
|---|---|
| Below 500 | Oropharyngeal and vulvovaginal candidiasis, tinea |
| Below 200 | Pneumocystis, oesophageal candidiasis |
| Below 150 | Histoplasma, Emergomyces, Coccidioides (below 250) |
| Below 100 | Cryptococcus, Talaromyces, disseminated histoplasmosis |
| Below 50 | Disseminated endemic mycoses, Emergomyces, mixed infection with tuberculosis |
Intensive care and surgery
Invasive candidiasis (central catheters, parenteral nutrition, broad spectrum antibacterials, abdominal surgery, anastomotic leak, necrotising pancreatitis) and invasive aspergillosis in patients with severe influenza, severe COVID-19, chronic obstructive pulmonary disease with corticosteroids, cirrhosis, and burns. Candida auris transmission and mucormycosis in diabetic and COVID-19 patients are also described.
| Group | Strategy |
|---|---|
| Acute myeloid leukaemia and myelodysplastic syndrome with intensive chemotherapy (neutropenia expected for more than 7 to 10 days) | Posaconazole delayed release tablets 300 mg twice daily on day 1, then 300 mg once daily (trough above 0.7 micrograms per mL, and above 1 for treatment), or voriconazole 200 mg twice daily (trough 1 to 5.5), or isavuconazole 372 mg every 8 hours for 6 doses, then 372 mg daily, in places where mould infection is frequent; liposomal amphotericin B or micafungin as alternatives |
| Allogeneic stem cell transplant with graft versus host disease or intensive immunosuppression | Posaconazole or voriconazole (mould active), during graft versus host disease treatment; fluconazole 400 mg daily or micafungin 50 mg daily in the neutropenic phase for those at low mould risk |
| Pre-engraftment in transplant | Fluconazole 400 mg daily (800 mg or 6 to 12 mg per kg in some regimens) or micafungin 50 mg daily (1 mg per kg in children) for yeast prophylaxis |
| Lung transplant | Universal prophylaxis: inhaled liposomal or lipid complex amphotericin B (for example liposomal amphotericin B 25 mg three times weekly, or 12.5 mg twice weekly) or itraconazole or voriconazole for 3 to 6 months, or longer in those colonised with Aspergillus, with voriconazole targeted therapy |
| Liver transplant at high risk (retransplant, renal failure, high transfusion, and choledochojejunostomy) | Fluconazole 400 mg daily, micafungin 100 mg daily, or liposomal amphotericin B 1 to 2 mg per kg daily for 2 to 4 weeks |
| Pneumocystis | Trimethoprim sulfamethoxazole, with indications according to the host group: HIV with CD4 below 200, allogeneic transplant, corticosteroid courses of 4 weeks or more, and purine analogue or alemtuzumab therapy |
| Cryptococcal antigenaemia in HIV | Screening of CD4 below 200 and fluconazole pre-emptive therapy (800 mg daily for 2 weeks, then 400 mg for 8 weeks, then 200 mg) |
| Histoplasmosis or talaromycosis in HIV in endemic regions | Itraconazole 200 mg daily in people with CD4 below 150 (histoplasmosis) or below 100 (talaromycosis) in very high incidence settings |
| Premature neonates | Fluconazole 3 to 6 mg per kg twice weekly for 6 weeks in those below 1000 grams (and in centres with a high rate of invasive candidiasis) |
| Intensive care | Not routine; targeted prophylaxis in selected high risk patients with recurrent gastrointestinal perforation or leakage |
Prophylaxis choices depend on the local epidemiology, the interactions with immunosuppressive drugs, and drug level monitoring. A mould active azole prevents mould infection but can select for resistant organisms, such as Mucorales, non albicans Candida with fluconazole resistance, and azole resistant Aspergillus fumigatus.
| Strategy | Details |
|---|---|
| Empirical therapy | Persistent or recurrent fever for 4 or more days in a high risk neutropenic patient despite broad spectrum antibacterials, and in those without mould active prophylaxis: caspofungin 70 mg on day 1, then 50 mg daily, micafungin 100 mg daily, or liposomal amphotericin B 3 mg per kg daily; it reduces progression, but is replaced in many centres by the pre-emptive strategy |
| Pre-emptive (diagnostic driven) therapy | Serial serum galactomannan (twice weekly in patients not on mould active prophylaxis), high resolution chest computed tomography, and early bronchoalveolar lavage, with treatment begun only on a positive trigger; equal survival with less drug use |
| Targeted therapy | After a diagnosis: voriconazole, isavuconazole, or liposomal amphotericin B for moulds, and an echinocandin or fluconazole for yeasts, according to the species |
| Patients on mould active prophylaxis | Serum galactomannan is not used for screening because the sensitivity is low; computer tomography and bronchoalveolar lavage are used instead, with a change of drug class and drug levels |
| Tool | Role |
|---|---|
| Chest computed tomography | Nodules, halo sign, reverse halo sign, cavities, air crescent, tree in bud, ground glass, consolidation, and pleural effusion; in neutropenic patients a negative scan has a high negative predictive value |
| Galactomannan | Serum (neutropenic haematology patients, sensitivity about 70 to 80 percent) and bronchoalveolar lavage (above 80 percent at an index of 1.0); lower in solid organ transplant and on mould active therapy; cross reactions with Fusarium, Talaromyces, Histoplasma, and some piperacillin products |
| Beta D glucan | Positive in invasive candidiasis, aspergillosis, pneumocystis pneumonia, and others; negative in Mucorales and Cryptococcus; false positives from immunoglobulin, albumin, and haemodialysis |
| Polymerase chain reaction | Aspergillus, Mucorales, Candida, and Pneumocystis on blood and bronchoalveolar lavage; azole resistance markers (cyp51A) |
| Cryptococcal antigen | Serum, plasma, and cerebrospinal fluid; screening in HIV |
| Histoplasma, Blastomyces, and Coccidioides antigens | Urine, serum, and cerebrospinal fluid |
| Culture | Blood cultures (Candida, Fusarium), bronchoalveolar lavage, tissue, and sterile fluids; susceptibility testing |
| Histology | The gold standard for proof, with attention to hyphae width, septation, and branching |
| Imaging of other organs | Sinus and brain computed tomography or magnetic resonance imaging, abdominal imaging, and eye examination (candidaemia) |
| Biopsy | Early biopsy (skin lesions, nodules) in the neutropenic patient |
| Interaction | Management |
|---|---|
| Azoles with calcineurin inhibitors | Voriconazole increases tacrolimus concentrations about threefold (reduce the tacrolimus dose to one third) and ciclosporin about twofold (reduce the dose by half); posaconazole increases tacrolimus about fourfold (reduce to one third); levels are checked every few days after starting and stopping the azole |
| Azoles with sirolimus and everolimus | Sirolimus is contraindicated with voriconazole and posaconazole in the label, and a dose reduction of 90 percent with careful monitoring is used when it cannot be avoided |
| Azoles with vinca alkaloids | Severe neurotoxicity with vincristine (avoid with itraconazole, posaconazole, and voriconazole; use an echinocandin or amphotericin B) |
| Azoles with ibrutinib, venetoclax, and midostaurin | Raised exposure of the targeted drug, so dose reduction (venetoclax is reduced by 50 to 75 percent with posaconazole), or an alternative antifungal |
| Azoles and QT prolongation | Electrocardiogram and electrolytes, with avoidance of other QT prolonging drugs (isavuconazole shortens the QT interval) |
| Rifampicin, rifabutin, phenytoin, carbamazepine, and phenobarbital | Lower voriconazole, itraconazole, and posaconazole levels (contraindicated with voriconazole), and lower isavuconazole levels; use amphotericin B or an echinocandin |
| Therapeutic drug monitoring | Voriconazole (trough 1 to 5.5 micrograms per mL, above 2 for severe disease), posaconazole (above 0.7 for prophylaxis, above 1 for treatment), itraconazole (above 0.5 for prophylaxis, 1 to 2 for treatment, by high performance liquid chromatography), flucytosine (peak 30 to 80 micrograms per mL) |
| Hepatic and renal toxicity | Azoles (liver), amphotericin B (kidney, potassium, magnesium), and echinocandins (rarely liver) |
| Drug absorption | Itraconazole capsules and posaconazole suspension need food and acid; the delayed release tablets are better; gastric acid suppressants lower absorption of some forms |
| Principle | Details |
|---|---|
| Reverse immune defects | Neutrophil recovery (granulocyte colony stimulating factor), reduction or withdrawal of corticosteroids and other immunosuppressants, correction of diabetes and acidosis, and antiretroviral therapy in HIV |
| Source control | Remove infected central venous catheters, surgical debridement or resection (pulmonary, sinus, skin, bowel), and drainage of abscesses |
| Antifungal choice | According to the pathogen, site, host, prior prophylaxis, interactions, and susceptibility |
| Duration | Aspergillosis, at least 6 to 12 weeks and until lesions resolve and immunosuppression ends; candidaemia, 14 days after the first negative culture; cryptococcosis, induction, consolidation, and maintenance (many months); secondary prophylaxis during further immunosuppression |
| Combination and salvage | Selected patients with refractory disease, with limited evidence |
| Monitoring | Clinical, imaging, and biomarker response, drug levels, and toxicity |
| Immune reconstitution | After neutrophil recovery or antiretroviral therapy, a paradoxical worsening of lesions can occur (fever, pulmonary nodules), and it is managed by continuing antifungal therapy and sometimes adding corticosteroids |
| Immunotherapy | Granulocyte transfusions, interferon gamma, and granulocyte colony stimulating factor in refractory infections, with limited evidence |
Outcome depends on the pathogen, the site, the speed of diagnosis, and recovery of immune function. Mortality of invasive aspergillosis in haematology patients is about 30 to 50 percent, of candidaemia 30 to 40 percent, of mucormycosis 40 to 80 percent, of fusariosis 50 to 80 percent, and of pneumocystis pneumonia in non HIV patients 30 to 60 percent.
A risk based programme combines the following measures:
- Environmental measures: high efficiency particulate air filtration and positive pressure rooms for allogeneic stem cell transplant and high risk haematology patients, and avoidance of construction, flowering plants, and soil contact.
- Hand hygiene and catheter care.
- Water filtration in units with fusariosis.
- Screening for cryptococcal antigen and tuberculosis in HIV.
- Nail and skin treatment before chemotherapy.
- Antifungal prophylaxis in defined risk groups.
- Antiretroviral therapy in HIV.
