|Year : 2015 | Volume
| Issue : 2 | Page : 41-47
Fungal pneumonia in intensive care unit: When to suspect and decision to treatment: A critical review
Shelley Shamim1, Abinash Agarwal2, Bijan Kumar Ghosh1, Mrinmoy Mitra1
1 Department of Chest Medicine, Calcutta National Medical College, Kolkata, West Bengal, India
2 Department of Chest Medicine, Midnapore Medical College, Medinipur, West Bengal, India
|Date of Web Publication||16-Jun-2015|
A-4 Pratiksha Apartment, Kaikhali, Sardarpara, Kolkata - 700 052, West Bengal
Source of Support: None, Conflict of Interest: None
Fungal pneumonia is classically found in neutropenic patients. There is increase in concern about this entity in nonneutropenic critically ill patients. Aspergillus is the main offending organism. Although Candida is frequently found in respiratory sample in intensive care unit (ICU) it is always colonization rather than pneumonia. Other than neutropenia, chronic obstructive pulmonary disease and long-term steroid use are the main risk factors for invasive pulmonary aspergillosis in an ICU setting. Treatment in a nonneutropenic patient is only considered if the culture of Aspergillus comes positive in respiratory sample in the background of risk factors.
Keywords: Fungal pneumonia intensive care unit, invasive fungal infection intensive care unit, invasive pulmonary aspergillosis, pulmonary candidiasis
|How to cite this article:|
Shamim S, Agarwal A, Ghosh BK, Mitra M. Fungal pneumonia in intensive care unit: When to suspect and decision to treatment: A critical review. J Assoc Chest Physicians 2015;3:41-7
|How to cite this URL:|
Shamim S, Agarwal A, Ghosh BK, Mitra M. Fungal pneumonia in intensive care unit: When to suspect and decision to treatment: A critical review. J Assoc Chest Physicians [serial online] 2015 [cited 2019 Mar 24];3:41-7. Available from: http://www.jacpjournal.org/text.asp?2015/3/2/41/158837
| Introduction|| |
Fungal pneumonia is classically found in neutropenic patients as in hematological malignancy and bone marrow transplantation. In these high-risk groups as in bone marrow transplantation, the incidence may be as high as 12-56%. ,, However, there is concern of having fungal pneumonia in intensive care unit (ICU) even in nonneutropenic patients. The question is whether this concern is really true and if it is so then by what extent. Whenever we come across a case of pneumonia in ICU there remains dilemma regarding starting antifungal agents especially if culture reports from respiratory secretions come positive for the fungus. Virtually Aspergillus and Candida are the main two culprits in ICU. However, they are often colonized normally in respiratory tract making the decision to treat difficult. Discrimination between colonization and infection is not easy and frequently, antifungal treatment is started in colonization leading to increased adverse events and costs. On the other hand, there is high mortality if treatment is delayed to confirm a definite diagnosis.
In this review, it was tried to evaluate the epidemiology of fungal colonization and pneumonia in ICU patients. Different diagnostic modalities and clinical prediction rules to detect invasive fungal pneumonia and the decision to treat were also reviewed.
Extensive literature search was conducted using PubMed, Google Scholar, Medline and Google Search using keywords like invasive pulmonary aspergillosis (IPA), pulmonary candidiasis, fungal pneumonia ICU, invasive fungal infection ICU. Review article, case reports and original articles published on this or related subjects were considered for this review.
| Epidemiology|| |
Candida, Aspergillus or rarely Zygomycetes (Mucorales) are the main fungi isolated in respiratory secretion in the ICUs. Isolation of Candida is by far common, found in 18-56% of intubated patients and up to 57% of bacterial pneumonia cases  whereas the incidence of aspergillosis is much lower and found in 6.3/1000 admissions.  Among candida Candida albicans is the frequent most species isolated (approximately 50%) followed by C. parapsilosis, C. tropicalis and C. glabrata. Aspergillus fumigatus is the most frequent isolate 80-90% cases of IPA. Other non-fumigatus species, like Aspergillus flavus or Aspergillus terreus and other filamentous fungi such as Mucorales, Fusarium, Scedosporium are by far less frequent.
While Candida is isolated from different body sites including respiratory samples, nearly all Aspergillus spp. come from respiratory samples.
| Candida Pneumonia and Disseminated Blood Stream Infection|| |
Approximately 10% of infections in an ICU are caused by Candida species. Most of the time they are blood stream infection from abdomen or iv lines or central venous catheter  Candida represent the fourth most pathogen isolated from blood cultures or deep-site infections in US causing 8-15%  of all bloodstream infections. Bloodstream candidal infection is frequent but not candidal pneumonia. Despite the frequent isolation of Candida from respiratory tract samples, antifungal is not recommended since pneumonia by this fungal species is exceptional.  The innate defense mechanisms of lungs make them relatively resistant to Candida invasion.  To diagnose pneumonia by Candida, it is required biopsy and demonstration of tissue invasion. In a recent study with 135 ICU patients with evidence of pneumonia in postmortem study (57% of them had bronchoalveolar lavage (BAL) or bronchial aspirate cultures positive to Candida in last 2 weeks), definitive diagnosis of pneumonia by Candida spp. was 0%. 
However, it should be taken into account that the presence of Candida in respiratory samples can be part of multifocal colonization found in other sites. Multifocal colonization, in the presence of risk factors, is associated with a high incidence of invasive blood stream candidiasis (not pneumonia).  If Candida comes positive in respiratory sample decision to give antifungal depends on an assessment of different high-risk factors for candidemia. And these are: (1) Peritonitis, (2) Abdominal surgery (prior abdominal surgery, especially when complicated by gastrointestinal tract perforations and anastomotic leaks), (3) Previous administration of broad-spectrum antibiotics, (4) Parenteral nutrition, (5) Multiple lumen catheters (central venous lines), (6) Prior Candida species colonization, (7) Renal replacement therapy, and (8) Mechanical ventilation. ICU patients with cancer have additional risk factors for candidaemia, such as chemotherapy-induced neutropenia, radiation-induced tissue injury, hematopoietic stem cell transplantation etc. These risk factors have become the cornerstone of empiric treatment of candidal infections in the ICU setting in order to reduce the high mortality rate associated with invasive candidiasis. ,
Several prediction models have been proposed with the help of these risk factors to detect patients with significant risk of having candidemia who may benefit from giving antifungals.
Ostrosky-Zeichner prediction rule
The rule was associated with a sensitivity of 34% and a specificity of 90%. If applied to ICU patients with sepsis (where chance of candidemia is around 10%) positive predictive value will be around 27.4% and negative predictive value of 92.4%. 
The Candida score
This is a more practical and useful bedside scoring system that allows early antifungal treatment when candidemia is suspected in nonneutropenic ICU patients. This "Candida score" is based on the predictive value of important risk factors. Using a logistic regression analysis the authors found several factors that are independently associated with an increased risk for proven candidal infection. The scores for the individual factors were: Parenteral nutrition (+0.908), prior surgery (+0.997), multifocal Candida colonization (+1.112), and severe sepsis (+2.038). A "Candida score" of >2.5 could accurately select patients who would benefit from early antifungal treatment (sensitivity 81%, specificity 74%).  PPV and negative predictive values are 25.4% and 98.7% respectively if the score is applied to sepsis patients with an incidence of candidemia of around 10%. So multifocal colonization (may be including respiratory tract colonization) if associated with severe sepsis or with two other risk factors then it mandates treatment with antifungals.
The clinical manifestations of invasive candidiasis in the ICU are similar to those of bacterial infections and range from protracted fever not responding to antimicrobials to a full-blown sepsis syndrome with multiorgan failure.  Blood culture results are positive in only 50% of invasive Candida however, if blood culture comes positive it always mandates treatment.
1,3β-D-glucan (BG) is a component of the cell wall of most fungi including Candida and Aspergillus (with the exception of Cryptococcus spp. and Zygomycetes). False positives have been described in patients under hemodialysis, in those treated with amoxicillin/clavulanic acid, azithromycin, albumin or glucans, and in Gram-positive bacteremia.  The use of BG detection has provided acceptable diagnostic values to screen invasive candidemia in onco-hematological patients with neutropenia and in high-risk ICU patients. A meta-analysis of studies evaluating assays for detection of BG in serum yielded a pooled sensitivity rate of 76.8% and a specificity rate of 85.3% for detection of invasive candidiasis. 
| Invasive Pulmonary Aspergillosis|| |
Aspergillus is the main fungus that we should bother as a cause of fungal pneumonia in the critically ill patient. Classically it's found in neutropenic patients. However, it is increasingly being found in general ICU patients with the immunosuppressive condition. Main risk factors for IPA in the ICU are previous treatment with steroids (odds ratio [OR]: 4.5, 95% confidence interval [CI]: 1.73-11) and chronic obstructive pulmonary disease (COPD) (OR: 2.9, 95% CI: 1.06-8.08)  as found in a study with 1753 patients admitted in 73 Spanish ICUs. Severe COPD treated with steroids is the most frequent comorbidity in hospitalized patients with IPA. 
Frequency of Aspergillus isolation from lower respiratory tract samples is 16.3 cases per 1000 hospitalized COPD patients (if 20% isolations have true IPA actual incidence of IPA in COPD is expected around 3 per 1000 hospitalized patients) and it was associated with heart insufficiency, antibiotic treatment within 3 months, accumulated steroid dose >700 mg (prednisone equivalent) within 3 months. ,
Hepatic transplantations, with an incidence of 1-9%, and pulmonary transplantation, with an incidence of 5-20%, are the solid organ transplantations that present, with the highest frequency of IPA. 
Principal risk factors for the development of IPA are summarized in [Table 1] and can be divided in high-, intermediate- and low-risk factors. 
|Table 1: Risk factors for invasive fungal infection in critically ill patients|
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Invasive pulmonary aspergillosis presents with fever, dyspnea, pleuritic chest pain, and hemoptysis. Hemoptysis is often found due to vascular thrombosis, which may raise suspicion especially in ICU patient.
Culture of Aspergillus
Collection of BAL sample is recommended for culture and galactomannan determination. BAL is the sample showing the highest sensitivity and specificity (50% and 97% respectively),  which increase if Aspergillus colony count is performed.  In addition, probability of IPA increases by the number of positive cultures to Aspergillus: 5.9% (1 culture), 18.4% (2 cultures) and 38.2% (≥3 cultures).  However, only 61% patients with confirmed IPA present with positive culture and 30-50% patients with IPA also have bacterial isolation in respiratory tract cultures , Identification of Aspergillus in respiratory samples may represent a simple colonization or be suggestive of IPA. The probability of being a true infection depends on the type of patient: 72% for patients with neutropenia  55% for solid organ transplant recipients  22% for COPD patients  and only 10% for general ICU cases.  The presence of Aspergillus in blood culture, perhaps with the exception of A. terreus 41, is not considered diagnostic since it usually means contamination.
A transbronchial biopsy may be done if the lesion is accessible and no gross hypoxemia. It can diagnose confirm IPA If fungal hyphae found in section or Aspergillus comes in culture. Similarly In peripheral lesion a computed tomography (CT) fine-needle aspiration cytology may be useful.
The galactomannan is a component of the cell wall of Aspergillus that is released during tissue invasion and is detected in serum, BAL, or cerebrospinal fluid. False positives have been described with beta-lactam treatment, mainly piperacillin-tazobactam, reducing the test specificity 43.  Positivity of serum galactomannan is considered when the index is >0.7 in a single sample. Validity of serum test for diagnosis depends on the type of patient, being the highest in the neutropenic patient with 85% sensitivity and 95% specificity. In patients with hematological malignancies sensitivity is 70%, in those with bone marrow transplantation it is of 80%, and lower in the case of solid organ transplantation (25-50%).  In ICU patients admitted due to COPD and IPA, positivity of two serum determinations presents a sensitivity of 41.7% and a specificity of 93.5%. 
Galactomannan in BAL is becoming of great utility, with an adequate diagnostic value in onco-hematological patients with neutropenia 47, 48 and in critically ill-patients. In this sense, in 110 critically ill patients (22% with neutropenia), using a cut-off value of 0.5, sensitivity and specificity in BAL was 88 and 87%, respectively, while sensitivity of galactomannan determination in serum was only 42%.  Similarly, in a Spanish study including 51 critically ill patients with a low number of neutropenic patients (11%), the most adequate cut-off value was 1, with100% sensitivity and 89.36% specificity for proven IPA. 
Utility of galactomannan in population with a low incidence of IPA as in ICU patients with moderate risk as mentioned above (where chance is around <5%) is not that well established. For example in COPD if the risk is assumed to be 1% a positive galactomannan will lead to the predictive value of around <10%. So, the decision to treat can't be taken on positive galactomannan test only. However, it is very useful in the high risk group (neutropenia).
Detection of nucleic acids by the polymerase chain reaction presents 88% sensitivity and 75% specificity for IPA diagnosis. The lack of a standardized method is the reason that it is still not in the diagnostic protocol.
Computed tomography scan
Computed tomography scan has also low utility in the critically ill patient since characteristic signs of IPA as the halo sign (central consolidation or nodule surrounded by ground glass opacity) and the air crescent sign (crescent shaped eccentric translucency in a nodule) are not frequent, around 5%) , a very low rate compared with 80% in neutropenic patients. So it has a good predictive value for diagnosis of invasive aspergillosis in neutropenic patients only. Pleural effusion is uncommon in IPA.
Different diagnostic criteria has been formulated to predict or diagnose IPA.
Criteria from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group: It continues to be the basis for diagnosis of IPA, classifying it as possible, probable or proven [Table 2]. Although this criteria was classically formulated for research purpose, but it is clinically useful in neutropenic patients, where there is a high risk of invasive aspergillosis, to predict the presence of IPA in an accurate way.  However, its utility in the ICU is limited. Absence in many cases of classical risk factors, of typical signs in CT scan or frequent negative results in the serum galactomannan test in nonneutropenic ICU patients makes this criteria useless in normal ICU patients. For this reason, several scales have been described as tools for IPA diagnosis and subsequent decision making in critically ill patients. Vandewoude et al.  analyzed 172 critically ill patients with the isolation of Aspergillus spp. from respiratory samples and proposed a diagnostic algorithm shown in [Table 3]. In this sense, a recent multicentre study has validated the  clinical algorithm proposed by Vandewoude et al. for IPA diagnosis. In that study, 524 critically ill patients with at least one endotracheal aspirate culture positive to Aspergillus spp. were included, 115 of them with histological data. Globally, positive and negative predictive values were 61% and 92%, respectively. When only COPD patients receiving prolonged steroid therapy were considered, positive and negative predictive values were 45% and 100%, respectively, for an IPA prevalence of 20% among patients with positive endotracheal aspirate culture.
|Table 2: Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria for IPA|
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Bulpa et al. established diagnostic criteria based on a revision of the literature on COPD patients with IPA that have not been validated in prospective series.  One of the problems of the algorithm is the requirement of a positive culture of a respiratory sample. IPA may be present in the absence of positive culture. However, until now there is no other sensitive tool to pick up accurately IPA cases from low prevalence ICU population. So, the treatment of IPA without culture isolation in nonneutropenic ICU patients is still not recommended. Galactomannan from BAL may have some utility in these situation, however current evidence is not sufficient to make an recommendation.
It cause respiratory infection mainly in neutropenic patients Mucormycosis is an opportunistic acute infection caused by fungi from the order Mucorales of the Zygomycetes class. The most frequent clinical presentation is rhinocerebral Mucormycosis followed by pulmonary infection. Risk factors include neutropenia, onco-hematological diseases, inadequately controlled diabetes mellitus, severe trauma, burns. The CT scan usually shows multiple nodular images and the so-called "reverse halo sign." Definitive diagnosis of Mucormycosis requires histological demonstration of tissue invasion. However, its isolation in the critically patient, especially if there are risk factors and compatible radiological image, should always lead to initiation of antifungal treatment.
| Recommendation for Critically Ill Patients|| |
- Candida in the respiratory sample even with consolidation radiologically is always colonization, so antifungal is not required
- Aspergillus in the respiratory sample without any risk factor [Table 1] chance of IPA is very rare. Most of the time (>98%) its colonization, so treatment is not required
- Aspergillus in respiratory sample/positive galactomannan + lung lesion in CT + High-risk group including neutropenic patient [Table 1] treatment is required
- High risk [Table 1] of aspergilosis + typical signs in CT (halo sign, crescent sign, nodules) consider antifungal
- Nonneutropenic intermediate risk [Table 1] (as in COPD with steroid use) patient + pneumonia in radiology + Aspergillus in respiratory sample - → consider antifungal
- Low-risk patients + pneumonia not responding to usual antibiotics + Aspergillus in respiratory sample → confirm by repeat FOB and preferably semiquantitative Aspergillus culture - → moderate or heavy growth - → start antifungal
- Candida in blood culture - give treatment
- Aspergillus in respiratory sample with severe sepsis - it's better to treat.
| Conclusion|| |
Although invasive aspergillosis is increasing in nonneutropenic ICU patient, its incidence is still very low and should be considered only in background of risk factor if Aspergillus culture comes positive. Candida pneumonia is virtually nonexistent, however Candida in respiratory sample may be a part of multifocal colonization and that in presence of other risk factors or sepsis mandates treatment.
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[Table 1], [Table 2], [Table 3]