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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 15  |  Issue : 2  |  Page : 59-65

Pulmonary mucormycosis: An anaesthesiologist's perspective


Department of Anesthesia and Pain Management, Sir H. N. Reliance Foundation Hospital and Research Centre, Mumbai, Maharashtra, India

Date of Submission04-Mar-2022
Date of Decision06-Apr-2022
Date of Acceptance06-Apr-2022
Date of Web Publication04-Jul-2022

Correspondence Address:
Ankit Ashok Gupta
467/75 Hussainbhai Mansion, Maulana Azad Road, 3rd Floor, Null Bazaar, Mumbai - 400 003, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hmj.hmj_26_22

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  Abstract 


Introduction: As a frontline warrior, every anesthesiologist is fighting the coronavirus 2019 (COVID-19) pandemic to save lives, but at the same time, post-COVID sepsis has emerged as a serious challenge opening a new battlefield for corona warriors. In recent times, mucormycosis, a rare opportunistic fungal infection, has emerged as a serious and life-threatening disease that is spreading rapidly, leading to tissue infarction and necrosis in post-COVID patients; hence, quick recognition of this potentially lethal disease and early treatment is of paramount importance in reducing the mortality rate. Methods: The aim of this review article was to summarise the literature on anesthestic management of pulmonary mucormycosis (PM) patients undergoing thoracotomy surgery. Searches had been conducted in Google Scholar, Wiley online library, National Library of Medicine, PubMed, Scopus, Excerpta Medica Database and Cochrane Library using the following keywords: lung, mucormycosis, anaesthesia, presurgical, intraoperative, postsurgical and their permutations. Results: The true frequency of mucormycosis in India is still unknown; however, it is found to be consequentially more than in Western nations. PM has a high mortality rate, which is attributable in part to its locally aggressive nature and in part to the underlying risk factors; however, this rate has improved over time due to advancements in diagnostic techniques. Conclusion: Management of PM must be approached with a multifaceted, assertive plan. Early identification of infection, reversal of the prevailing risk factors, surgical elimination of contaminated tissue and medical management by antimycotic agents are the four critical steps in the management of mucormycosis. The key to a successful operation was a thorough pre-operative assessment, proper pre-operative preparation and much clinical surgical expertise.

Keywords: Amphotericin B, coronavirus 2019, double-lumen tube, lobectomy, mucormycosis, pulmonary


How to cite this article:
Gupta AA, Deshmukh AN, Koli DC, Mehta HH. Pulmonary mucormycosis: An anaesthesiologist's perspective. Hamdan Med J 2022;15:59-65

How to cite this URL:
Gupta AA, Deshmukh AN, Koli DC, Mehta HH. Pulmonary mucormycosis: An anaesthesiologist's perspective. Hamdan Med J [serial online] 2022 [cited 2022 Aug 10];15:59-65. Available from: http://www.hamdanjournal.org/text.asp?2022/15/2/59/349779




  Introduction Top


Moreover, a year ago, a cluster of pneumonia cases sparked global alarm, and the culprit infection was identified as 2019-nCoV, a new coronavirus. This virus had the unusual property of swiftly spreading from a single city to the entire country in approximately a month, prompting it to be labelled a pandemic. Patients suffering from this viral infection exhibit a vast spectrum of symptoms spanning from mild in approximately 80% to severe illness with a case fatality rate of approximately 2%. One of the late sequelae of coronavirus disease that got to the fore due to its impact on morbidities and mortality in severe disease types is an invasive fungal disease.

The human body is not the usual habitat for fungi that belong to the order Mucorales and our immune system generally defends us against such opportunistic infections; however, the 'internecine triune' of diabetes mellitus (DM), coronavirus-2019 (COVID-19) and steroid therapy can erode a person's immunity to the point where these opportunistic infections can prevail. In India, high blood sugar (DM) is the most predominant implicit predictor for mucormycosis, as opposed to bone marrow and organ transplant patients in industrialised regions.[1]

Paltauf[2] initially identified zygomycosis in the 19th century, and Baker[3] popularised the term Mucormycosis in the 20th century for a very rare angioinvasive illness marked by tissue infarction and necrosis, as well as a pestilential infection, which affects primarily immunocompromised people.

Respiratory invasion is the predominant presentation of mucormycosis in India, after rhino-orbital-cerebral (ROCM) infection, and has emerged as an inexorably important and catastrophic consequence of an aggressive fungal infection in several regions globally during the COVID era.[4]


  Evidence Acquisition Top


This review includes studies involving pulmonary mucormycosis (PM) patients undergoing thoracotomy surgery. Searches have been conducted in Google Scholar, Wiley online library, National Library of Medicine, PubMed, Scopus, Excerpta Medica Database and Cochrane Library using the terms lung, mucormycosis, anaesthesia, presurgical, intraoperative, postsurgical and their permutations.


  Mycology Top


The taxonomical classification of mucormycosis is shown in [Table 1]. Although there are other genera in the Mucorales that may infect humans, most mucormycosis infections are caused by members of the Rhizopus or Mucor genera.[5]
Table 1: Taxonomical classification of mucormycosis

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  Pathogenesis Top


SARSCoV2 infection alters helper T-cells and cytotoxic T-cells, and as documented in the most severe cases of COVID19, this decrease in lymphocytes, particularly T-cells, puts patients at greater risk for opportunistic infections, attributing to fungal infections for the majority of case reports.[6] Dysfunction of the alveolar macrophages in the airways, along with this lymphopenia, can lead to mucormycosis, an opportunistic fungal infection caused by micromycetes.[7]

Mucormycosis clinical manifestations are characteristically based on anatomic location, such as ROCM, lungs, intestine, skin, kidney, disseminated mucormycosis and other miscellaneous forms, which include infection of the urinary bladder, ear, cardiac, lymph nodes, parotid gland, bones and uterus.[8]


  Epidemiology Top


Mucormycosis presents as the third-most intrusive and potentially fatal opportunistic illness in people of all ages.[9] According to the analysis for the year prior to COVID, the worldwide incidence of mucormycosis spanned from 5 to 1700 per billion people, with India being comparatively 80 times higher (140 per million people) than affluent regions.[10] Mucormycosis death rates in India vary from 28% to 52%, with an ultimate mortality rate of 50%–70% for PM, although it can reach 95% in diffused PM.[10],[11]


  Risk Factors Top


Mucormycosis has a very strong causal association with uncontrolled DM, as high blood glucose concentrations promote the development of this fungus. The prevalence of DM in mucormycosis in different countries is shown in [Table 2].[12]
Table 2: Prevalence of diabetes mellitus in mucormycosis worldwide

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Male, handicraft workers with low education and living in low socio-economic conditions were more susceptible to PM.[13] The other associated risk factors commonly linked to PM are shown in [Table 3].[14]
Table 3: Prevalence percentage of mucormycosis in various conditions

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Iron overload and the use of deferoxamine, an iron and aluminium chelator, are two more variables that encourage the growth and pathogenicity of mucormycosis. Deferoxamine, which was once prescribed in renal failure patients to treat aluminium overload, is now infrequently found. Iron overload usually occurs in people who have received several blood transfusions, necessitating the use of deferoxamine to chelate iron. This results in the production of Ferrioxamine, a siderophore that promotes fungal growth.[15]

Clinical features

PM often manifests with nonspecific symptoms such as fever, cough and dyspnoea, as well as constitutional signs such as weight loss and night sweats in rare cases. Based on the severity of the invasion of the fungus, patients may present in a variety of ways, i.e., when the infection spreads to the pleura, it leads to pleural thickening and effusion presenting as pleuritic chest pain and when the infection spreads to the chest wall and rib, the patient presents with chest wall tenderness and subcutaneous emphysema. In patients where mucormycosis reaches the upper pleuro-pulmonary groove, destroying the thoracic aperture and involving the brachial plexus and inferior cervical ganglion (Stellate ganglion), it can manifest as Pancoast syndrome and Horner's syndrome.[16] Angioinvasion of the blood vessel presents as haemoptysis, and is catastrophic when involving a large artery or vein. The infiltration of the trachea and main bronchus by mucormycosis is infrequent, although more frequently seen in DM patients with superior lobe preference, followed by the mainstem bronchi and finally the trachea. Endobronchial mucormycosis lesions can cause severe airway obstruction, manifesting as obstructive airway symptoms.[17]


  Diagnosis Top


Considering the constraints of imaging investigations, diagnosing PM is a challenging task that nearly always necessitates a strong sense of presumption and quite often requires the histopathologic affirmation of fungal intrusion of the tissues. On histological examination, PM is recognised as a hyphal intrusion in major and minor arteries, causing occlusion and ischaemia, and lesions demonstrate varying levels of neutrophil permeation based on the extent of neutropenia.[18] Since the pathogenic organism here is pervasive, may inhabit healthy persons and is a frequent laboratory pollutant, isolating the fungus from a potentially suspected area is seldom adequate to determine the presence or absence of mucormycosis. Both bronchoscopic and percutaneous lung biopsy procedures are useful for obtaining tissue samples for analysis; however, the bronchoscopic method can help in diagnosis in individuals with endobronchial PM infiltration.

Initially, molecular diagnostics were performed using the same materials as cultures, namely tissue and bronchoalveolar lavage fluid. Mucorales DNA may now be identified using quantitative polymerase chain reaction, which does not require any invasive sample collection procedures and can be performed with plasma, serum or even urine, making the test non-invasive. These tests, however, are difficult to get.[19]

In this condition, radiographic results lag behind clinical development, and a negative imaging examination does not justify deferring more aggressive diagnostic techniques in patients with strong clinical suspicion of the disease. The much more prevalent radiological feature on the chest radiography is lobar and segmental consolidation, and it can be multilobar in certain people.[20] CT characteristics of disease differ considerably and might present with the halo sign [Figure 1]a or the reverse halo sign [Figure 1]b. Kuhlman et al. originally reported the halo sign, which histopathologically is a pulmonary infarction with alveolar haemorrhage surrounding, i.e., on imaging, the core region of necrosis is seen as a nodule, and the bleeding around the nodule is seen as a halo of ground-glass attenuation. This feature can only be seen during the first fortnight of the infection and would not be detected beyond 2 weeks.[21] On histopathological examination, when the infarcted lung tissue has more haemorrhage at the periphery than at the core, it is seen as a distinct radiological sign, portrayed by Kim et al. as a reverse halo sign, featuring as the central spherical area of ground-glass opacity encircled by a crescent or complete ring of consolidation.[21]
Figure 1: (a) Halo sign and (b) Reverse halo sign

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  Treatment Top


Antifungals

Due to the rarity of mucormycosis, there have been no randomised trials testing the efficacy of antifungal regimens, and the paucity of published clinical data makes it difficult for us to choose among the various antifungal drugs presently available to treat this fungal infection and the list of antifungal available to us for the same are described in [Table 4].[17]
Table 4: List of antifungals used in the treatment of mucormycosis

Click here to view


Amphotericin B deoxycholate (AMP-B) is the medication of choice for mucormycosis and the lipid formulation of AMP-B is more preferred to deliver a higher dose with less chance of nephrotoxicity. Retrospective clinical data clearly suggest liposomal AMP-B being a cut above amphotericin B deoxycholate however provides no clear conclusions about the relative effectiveness and safety of liposomal AMP-B against AMP-B lipid complex.[22]

Posaconazole and isavuconazole are second-line prescriptions in the therapy of PM and are always given along with the first-line medications. They are prescribed as an abdicate remedy in patients who show improvement with AMP-B and may need a prolonged oral course of treatment with these drugs. If individuals show no improvement with AMP-B or are intolerant to AMP-B, these drugs play the role of salvage therapy.[23]

Caspofungin, anidulafungin and micafungin have no role as a monotherapy and are always prescribed in combination with AMP-B.[24]

Surgical debridement

Patients with PM had a dismal overall survival rate, but those who had pulmonary resection surgery had a much greater survival rate. As a result, making a prompt choice to have lung resection may be critical for improving outcomes in patients with PM, and more surgical-focused therapy options should be considered for these individuals.

Surgery is advised for individuals with limited illness since it improves outcomes when compared to antifungal medication alone.[25] Surgery, which might include wedge resection, lobectomy or pneumonectomy, is typically curative in people with little lung involvement, but in patients with considerable lung involvement, surgery may not be viable. Although surgery for bilateral illness is unusual, it has been found to be helpful in controlling the source of the disease.[26]

Debulking surgery consisting of the removal of infective and necrotic tissue removal has been substantially shown to enhance survival in anecdotal clinical reviews.

Anaesthetic management

Mucormycosis is characteristically seen in immunocompromised patients, and hence, the most important concern in the peri-operative phase is to maintain strict asepsis.

Pre-operative concerns

Mucormycosis being an opportunistic infection, optimising the underlying predisposing variables and, where possible, eliminating these predisposing factors is essential to achieve the desired result after surgery. Two of the most prevalent predisposing factors encountered with mucormycosis are uncontrolled hyperglycaemia and pulmonary tuberculosis, and both these factors have a significant effect on post-operative recovery as uncontrolled blood sugar increases the incidence of secondary infections, whereas patients with pulmonary tuberculosis frequently have poor nutrition, which hampers their surgical recovery.

In patients taking AMP-B, hypokalaemia and hypomagnesaemia are common electrolyte abnormalities that can induce arrhythmias; however, potassium correction should be done with caution as more than 80% of these patients also develop renal impairment and about 15% of these patients require haemodialysis.[27] Coagulation disturbances, haemodynamic instability and respiratory aberrancies are other features seen in patients on amphotericin-B with renal failure, which may need optimisation preoperatively.

Intraoperative concerns

Maintenance of systolic and diastolic blood pressure and myocardial contractility is of utmost importance to avoid the development of acute renal failure in these already renal compromised patients. Hypotension can occur either during induction of anaesthesia or with major intraoperative blood loss as mucormycosis may present with vascular invasion, tissue necrosis and severe adhesions in the chest wall, diaphragm and mediastinum, thereby increasing the difficulty of surgery as well. These patients require intermittent arterial blood gas analysis to watch for metabolic derangements, fluid–electrolyte balance and, if needed later, thromboelastography to look for coagulation abnormalities.

The surgical plan for PM either consists of lobectomy or in some cases pneumonectomy where the infection is not limited to a single lobe. For providing requisite access for surgery, one-lung ventilation is delivered either by a bronchial blocker (BB) or by a double-lumen tube (DLT). The decision to use a BB or DLT is based on the extent of infection with involvement of surrounding structures, presence of bleeding and the need to protect contralateral healthy lung tissue from spillage during surgery.

Propofol, a commonly used induction agent, has a high pro-microbial proliferation propensity for bacteria as well as for fungi. Many studies have shown bloodstream infections, surgical wound infections and acute febrile illness attributed to propofol-related bacterial and fungal infections.[28] Hence, the use of propofol should be done with strict asepsis during the handling and storage of the drug to prevent secondary infections in these immunocompromised mucormycosis patients. Another issue to be concerned about while using propofol, as an induction agent, is the possibility of a fall in mean arterial pressure, which might increase renal damage.

Ketamine, on the other hand, maybe the preferred induction agent in these individuals since it preserves mean arterial pressure and has antibacterial and antifungal characteristics, reducing the risk of secondary infections.[29] Although etomidate can be an efficient induction drug for maintaining blood pressure, its adrenal suppression impact increases perioperative morbidity and death in immunocompromised individuals.

Numerous inhalational agents are said to have bactericidal and fungicidal properties; nevertheless, there is almost no agreement about the best inhalational agent to be used in patients with PM.[30] Lidocaine has been shown to have antifungal activity, being fungi-static at low doses and fungicidal at increased doses; however, this antifungal effect on mucormycosis warrants further exploration.[31]

Antifungals have a significant impact on the pharmacokinetics of benzodiazepines and opioids. The action of oral midazolam is significantly extended due to antifungals, with strong hypnotic effects; surprisingly, there is only mild prolongation of action with intravenous bolus doses of midazolam.[32] Similarly, antifungals limit fentanyl clearance and are linked with a considerable lengthening of elimination half-life, creating a risk of respiratory depression when administered as an infusion or via a transdermal route. Voriconazole, when delivered in typical therapeutic dosages, reduces fentanyl clearance by approximately 28%, but there is no comparable evidence with the use of posaconazole.[33]

Antifungals, in and of themselves, have no influence on the elimination half-life of muscle relaxants; nonetheless, they cause hypokalaemia, which can lengthen the duration of the muscle relaxant. Few antifungals are strong inducers of cytochrome P450 enzymes, which metabolise steroidal muscle relaxants to some extent, necessitating higher doses for effective action.[34]

Post-operative concerns

Despite major breakthroughs in pre-surgical assessment, operative procedures, anaesthetic administration and post-operative care, morbidity and death probability post-surgery endure to be tremendous, particularly in patients with mucormycosis who present with co-existing disseminated infection and multi-organ dysfunction due to immunosuppression. Intraoperative use of blood and blood products and inotropic support requirements are the factors affecting the length of stay in intensive care units (ICU). One of the most common causes of prolonged ICU stay and readmission to ICU in patients undergoing thoracic surgery is acute respiratory distress syndrome (ARDS). The incidence of ARDS is classified depending on the type of surgery, i.e., 3.8%–7.9% after pneumonectomy, 1.9%–2.96% after lobectomy/bilobectomy and 0.7%–3.2% after sublobar resection.[35] These rates are further increased in mucormycosis patients, considering that they are more prone to opportunistic infections per se.

Pain treatment following a thoracotomy necessitates a multimodal strategy that includes both localised and systemic analgesics, as shown in [Table 5].[36] The choice of pain relief modality must be based on after weighing the potential benefits and challenges of a personalised approach, and must be tailored as per the patient's physical status and desires, the magnitude of the operation and the in-house facilities available.
Table 5: Modes of post-operative analgesia

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  Conclusion Top


The true frequency of mucormycosis in India is unknown; however, it is thought to be consequentially more than in Western nations. PM has a high mortality rate, which is attributable in part to its locally aggressive nature and part to the underlying risk factors; however, this rate has improved over time due to advancements in diagnostic techniques and it must be approached with a multifaceted, assertive plan. Early identification of infection, reversal of the prevailing risk factors, surgical elimination of contaminated tissue and medical management by antimycotic agents are the four critical steps in the management of mucormycosis. The key to a successful operation was a thorough pre-operative assessment, proper pre-operative preparation and much clinical surgical expertise.

Highlights

  • Mucormycosis is the third-most invasive and fatal opportunistic infection
  • The most frequent risk factor linked with mucormycosis is diabetes mellitus
  • Diagnosing PM is a challenging task, and requires histopathologic evidence
  • Amphotericin B is the medication of choice for mucormycosis
  • Anaesthetic management for PM has to be curtailed as per the patient's presentation and the plan of surgery.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Abstract
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Mycology
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