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Abstract

Background and aims:

The presence of fungal infections has been described in patients after recovering from COVID-19. This study aims to conduct a systematic review of studies that reported fungal infections (Mucor spp., Pneumocystis jirovecii, or Aspergillus spp.) in adults after recovering from COVID-19.

Methods:

We performed a systematic review through PubMed, Web of Science, OVID-Medline, Embase, and Scopus. The study selection process was performed independently and by at least two authors. We performed a risk of bias assessment using the Newcastle–Ottawa Scale for cohort and case–control studies, and the Joanna Briggs Institute’s Checklists for Case Series and Case Reports.

Results:

The systematic search found 33 studies meeting all inclusion criteria. There was a total population of 774 participants, ranging from 21 to 87 years. From them, 746 developed a fungal infection. In 19 studies, Mucor spp. was reported as the main mycosis. In 10 studies, P. jirovecii was reported as the main mycosis. In seven studies, Aspergillus spp. was reported as the main mycosis. Regarding the quality assessment, 12 studies were classified as low risk of bias and the remaining studies as high risk of bias.

Conclusion:

Patients’ clinical presentation and prognosis after recovering from COVID-19 with fungal infection differ from those reported patients with acute COVID-19 infection and those without COVID-19 infection.

Keywords

aspergillosis COVID-19 fungal infections mucormycosis

Introduction

Nearly 4 years have passed since coronavirus disease (COVID-19) emerged, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since then, despite the significant progress in immunizations against COVID-19, multiple variants of SARS-CoV-2 have been detected that have decreased the effectiveness of the vaccines, making disease control still not possible.^1,2 Likewise, although the majority of SARS-CoV-2 infections are currently not fatal, people who recovered from an infection, even those people who had mild COVID-19 may present physical and neuropsychiatric symptoms that continue or develop after an acute COVID-19 infection (4 weeks or more after the initial phase) as part of a syndrome called ‘Long COVID’ (LC).³ Its frequency ranges from 10% to 30% in patients who were managed as outpatients and up to 76% in hospitalized patients,⁴ and it is estimated that approximately 100 million people are already with LC worldwide. An economic burden of 2.6–3.7 billion dollars has also been estimated, which includes reduced quality of life, absenteeism from work, and potential reduction in income.⁵ It can affect any age, but the majority of cases are in patients between 36 and 50 years old who suffered a mild COVID-19 illness and were not hospitalized. LC can manifest in multiple ways in different systems, including cardiovascular, cerebrovascular, and gastrointestinal diseases, thrombotic phenomena, chronic fatigue syndrome, and dysautonomia, such as postural orthostatic tachycardia syndrome.⁶ It is postulated that the pathogenesis of LC is secondary to immune dysregulation, microbiota alteration, autoimmunity, endothelial abnormalities, and dysfunctional neurological signaling.

It has been reported that these LC patients present persistent immunological dysfunction, characterized by highly active innate cells, depletion of B and T cells (including CD4 and CD8 T lymphocytes), and high expression of Interferon (IFN)-β and IFN-λ1.^7,8 Generally, CD4+/CD8+ T lymphocytes produce IFN-γ, which is a potent promoter of the fungicidal activity of macrophages⁹; this CD4 lymphopenia can last even 75 days after acute infection¹⁰; hence, its depletion could be related to a greater risk of infections such as Mucormycosis, Cryptococcosis, and P. jirovecii in patients recovered from COVID-19.

Furthermore, numerous studies have reported a significant increase in invasive fungal infections in patients with COVID-19, such as invasive candidiasis, pulmonary aspergillosis, Mucormycosis, and, less frequently, Pneumocystosis, Coccidioidomycosis, Histoplasmosis, cryptococcosis, and Fusariosis,^11–13 mainly in severely ill patients.¹⁴ In the United States, the prevalence of patients hospitalized for fungal infections increased by approximately 9% annually between 2019 and 2021 after the start of the COVID-19 pandemic.¹⁵ COVID-19 may be a risk factor for certain fungal infections, mainly those caused by filamentous fungi, and this is probably due to a deregulation of the immune system and immunosuppressive therapies such as corticosteroids.¹⁶ During the pandemic, patients with COVID-19 and fungal co-infection had a mortality of 48.5% compared to 12.3% in patients with fungal infection not associated with COVID-19. They also had a more extended hospital stay and a greater need for intensive care, and mechanical ventilation (MV).¹⁷

Most of these infections occurred in the acute period of the disease. Nevertheless, the presence of fungal infections has also been described in patients after recovering from COVID-19, which has not been well characterized. This study aims to conduct a systematic review of studies that reported fungal infections (Mucor spp., Pneumocystis jirovecii, or Aspergillus spp.) in adults after recovering from COVID-19.

Methods

Register and report guidelines

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.¹⁸

Search strategy and databases

The search formula was built using MeSH, Emtree, and free terms of the keywords of our research question. Then, it was adapted for all databases. No type of search restriction was applied to this systematic review. We attached the complete search strategy for each database as Supplemental Material (Supplemental Table S1). Our entire search strategy followed the Peer Review of Electronic Search Strategies guidelines.¹⁹ Systematic search was run on 10 September 2023 in all databases (PubMed, Web of Science, OVID-Medline, Embase, and Scopus).

Eligibility criteria

We searched studies that reported fungal infection (Mucor spp., P. jirovecii, or Aspergillus spp.) in adults after recovering from COVID-19. Our inclusion criteria were as follows: (i) studies conducted in adult patients (⩾18 y/o) after recovering from COVID-19. We excluded editorials, comments, letters to the editor, conference abstracts, or posters of congresses, due to the risk of bias cannot be assessed in these types of publications.

Study selection process and data extraction

Duplicates were removed by EndNote v20.6© and Rayyan QCRI (Rayyan Systems Inc©).²⁰ Screening by title and abstract and full-text assessment were also performed with Rayyan QCRI. Any stage of the study selection process was performed independently by at least two authors. Any conflict or discrepancy concerning the inclusion of studies at any stage of the study selection process was resolved until consensus. Two authors independently performed data extraction in a pre-set Google Sheets©. In the same way, any conflict was resolved by consensus or by a third author. Extracted data were as follows: first author, publication date, study title, study design, study location, sample size, age, sex, and clinical characteristics of these patients.

Risk of bias

We performed a risk of bias assessment using the Newcastle–Ottawa Scale (NOS) for cohort and case–control studies.²¹ Risk of bias was categorized as follows: low risk of bias (⩾7 stars) or high risk of bias (<7 stars). Case reports and case series were assessed with the Joanna Briggs Institute’s Checklist for Case Series and Checklist for Case Reports, respectively.²² As with the NOS-C and the NOS, the cutoff points for both checklists were seven stars.

Results

The search conducted in the databases resulted in 1282 articles, of which 33 met the inclusion criteria^23–55 (Figure 1). The reviewed articles are summarized in Table 1.

Figure 1.

PRISMA flow diagram.

Table 1.

Characteristics of the included studies.

Author	Year	Country	Age	Participants (male/female)	Patients recovered from COVID-19 with fungal infection evaluated	Identified fungal pathogen	Time elapsed between recovery from COVID-19 and fungal infection	Degree of severity presented when having COVID-19	Medical diagnosis or infection site	Important clinical history	Diagnostic method	Antifungal therapy	Outcome
Ahmed et al.	2022	Egypt	58 ± 12	21 (11/10)	21	Mucor spp.	14 days	NR	Oral mucormycosis: 21/21	NR	NR	NR	NR
Al-Jumaily et al.	2023	Iraq	57.33 ± 11.6	15 (9/6)	15	Mucor spp.	NR	Severe COVID-19: 6/15 Non-severe COVID-19: 9/15	Sinusitis: 15/15	Diabetes mellitus: 7/15 Diabetes-like syndrome during COVID-19 infection: 5/15	Histopathological examination from affected areas	Surgical intervention + IV Meropenem + IV Liposomal amphotericin B + IV metronidazole (8/15) Surgical intervention + IV Meropenem + IV metronidazole (2/15) Surgical intervention + IV Meropenem + IV Liposomal Amphotericin B + IV Metronidazole (5/15)	NR
Alsayed et al.	2022	Jordan	45.35 ± 12	31 (12/19)	3	P. jirovecii	NR	Non-severe COVID-19: 3/3	P. jirovecii pneumonia	Asthma: 3/3 Diabetes mellitus: 2/3	qPCR	NR	Discharged: 2/3 Deceased: 1/3
Amparo-Vicente et al.	2022	Spain	71	1 (1/0)	1	P. jirovecii	5 days	Severe COVID-19	P. jirovecii pneumonia	Hypertension and ischemic cardiopathy	qPCR	IV Cotrimoxazole + IV corticosteroids	Patient discharged
Anto et al.	2023	India	48.42 ± NR	110 (78/32)	110	Mucor spp.	NR	NR	Rhinosinusitis	Diabetes mellitus: 98/110	Histopathological examination from affected areas	Surgical intervention + IV Liposomal Amphotericin (110/110)	Discharged: 104/110 Deceased: 6/110
Ayub et al.	2021	Pakistan	49.7 ± 23.9	4 (2/2)	4	P. jirovecii	NR	NR	P. jirovecii pneumonia	Hypertension: 2/4 acute myeloid leukemia: 1/4 Diabetes mellitus: 1/4	Bronchoalveolar lavage	IV cotrimoxazole + IV Corticosteroids (3/4) NR (1/4)	Discharged: 3/4 Deceased: 1/4
Bachchan et al.	2021	India	70	1 (1/0)	1	Mucor spp.	25 days	NR	Sinusitis	Diabetes mellitus	Histopathological examination and culture samples from affected areas	IV Amphotericin B	Death
Baig et al.	2022	Pakistan	59	1 (1/0)	1	Aspergillus spp.	NR	Severe COVID-19	Invasive pulmonary aspergillosis	Hypertension, hyperlipidemia, and pulmonary hypertension	Serum galactomannan testing and culture samples from affected areas	IV Isavuconazole	Patient discharged
Bhopalwala et al.	2022	United States	56	1 (0/1)	1	Aspergillus spp.	6 months	Severe COVID-19	Invasive pulmonary aspergillosis	Diabetes mellitus, obesity, asthma, hypertension, obstructive sleep apnea, seizure disorder, and coronary artery disease	Serum galactomannan testing and histopathological examination	IV Itraconazole	Patient discharged
Bonates et al.	2021	Brazil	56	1 (0/1)	1	Mucor spp.	14 days	Non-severe COVID-19	Rhino-orbital cerebral mucormycosis	Diabetes mellitus	Histopathological examination and culture samples from affected areas	IV Amphotericin B	Death
Chakravarthy et al.	2021	India	75	1 (1/0)	1	P. jirovecii	NR	NR	P. jirovecii pneumonia	Hypertension and diabetes mellitus	Serum beta-d-glucan and clinical findings	IV Cotrimoxazole	Patient discharged
Elguera-Falcón et al.	2020	Peru	45–51	4 (3/1)	4	Mucor spp.	NR	NR	Rhinocerebral mucormycosis: 4/4	Hypertension: ¼ Diabetes mellitus: 4/4	Histopathological examination and culture samples from affected areas	IV Amphotericin B + IV Isavuconazole (3/4) IV Amphotericin B (1/4) Surgical debridement (2/4)	Patients discharged: 4/4
Gentile et al.	2021	Italy	59 ± 8	5 (4/1)	5	P. jirovecii	NR	Severe COVID-19: 4/5 Non-severe COVID-19: 1/5	P. jirovecii pneumonia	NR	Immunofluorescence assay	IV Cotrimoxazole + IV Corticosteroids (5/5)	Patients discharged: 5/5
Hamadeh et al.	2022	Lebanon	45–74	2 (2/0)	2	Mucor spp.	NR	NR	Rhinosinusitis mucormycosis: ½	Diabetes mellitus: 2/2 Hypertension: ½	Clinical and radiological findings Histopathological examination and culture samples from affected areas	IV Cotrimoxazole + IV Corticosteroids	Discharged: ½ Deceased: ½
Hamadeh et al.	2022	Lebanon	45–74	2 (2/0)	2	Aspergillus spp.	NR	NR	Rhinosinusitis Aspergillosis: ½	Diabetes mellitus: 2/2 Hypertension: ½		IV Cotrimoxazole + IV Corticosteroids	Discharged: ½ Deceased: ½
Hamed et al.	2022	Palestine	34	1 (0/1)	1	Mucor spp.	30 days	Severe COVID-19	Rhino-orbital-cerebral mucormycosis	Gestational diabetes	Histopathological examination and culture samples from affected areas	Surgical intervention + IV Liposomal amphotericin B (4/4)	Death
Jayakeerthy et al.	2022	India	31–75	30 (17/13)	30	Mucor spp.	7–60 days	NR	Rhino-orbital mucormycosis: 28/30 orbito-facial mucormycosis: 1/30 Rhino-sinusoidal mucormycosis: 1/30	Diabetes mellitus: 28/30	Histopathological examination and culture samples from affected areas	Surgical intervention + IV Liposomal amphotericin B (6/6)	NR
Jhunjhunwala et al.	2021	India	40–74	4 (4/0)	4	Mucor spp.	NR	NR	Rhino-orbital mucormycosis: 4/4	Hypertension: 4/4 Diabetes mellitus: 4/4	Histopathological examination from affected areas	Surgical intervention + IV Liposomal amphotericin B (14/14)	Patients discharged: 4/4
Kesarwani et al.	2022	India	51.33 ± 11.99	6 (5/1)	6	Mucor spp.	NR	Severe COVID-19: 1/6 Non-severe COVID-19: 5/6	Sinusitis: 6/6	Hypertension: 2/6 Diabetes mellitus: 5/6	qPCR	IV Cotrimoxazole + IV Corticosteroids	Patients discharged: 6/6
Khorasani et al.	2023	Iran	56 ± 13.6	14 (3/11)	14	Mucor spp.	12.79 ± 9.2 days	NR	Rhinocerebral mucormycosis: 14/14	Hypertension: 4/14 Diabetes mellitus: 11/14 Acute myeloid leukemia: 1/14	Immunochromatographic assay and culture samples from affected areas	Oral Itraconazole	Discharged: 11/14 Deceased: 3/14
Kim et al.	2022	South Korea	48	1 (1/0)	1	P. jirovecii	14 days	NR	P. jirovecii pneumonia	Good syndrome	qPCR	IV Cotrimoxazole + IV Linezolid IV + Corticosteroids	Patient discharged
Kuate et al.	2022	Cameroon	63	1 (0/1)	1	Aspergillus spp.	13 months	Severe COVID-19	Chronic pulmonary aspergillosis	NR	Histopathological examination and culture samples from affected areas	Surgical intervention (200/200)	Patient discharged
Lago-Rodríguez et al.	2022	Spain	87	1 (0/1)	1	P. jirovecii	14 days	Severe COVID-19	Sepsis and P. jirovecii pneumonia superinfected with methicillin-resistant Staphylococcus aureus	Diabetes mellitus, hypertension, and coronary heart disease	Histopathological examination and culture samples from affected areas	Surgical intervention + Oral Posaconazole	Death
Lakshmi et al.	2023	India	21–80	200 (132/68)	200	Mucor spp.	NR	NR	Sinusitis: 197/200 Cranial involvement: 2/100 Skin involvement: 1/200	Hypertension: 70/200 diabetes mellitus: 162/200	Histopathological examination from affected areas	NR	Discharged: 169/200 Deceased: 31/200
Madala et al.	2022	India	41	1 (1/0)	1	Aspergillus spp.	NR	NR	Laryngeal aspergillosis	No comorbidities	qPCR	IV Cotrimoxazole	Patient discharged
Madhumitha et al.	2022	India	64	1 (1/0)	1	Mucor spp.	NR	NR	Renal mucormycosis	Hypertension and diabetes mellitus	qPCR	IV Cotrimoxazole + IV Corticosteroids	Death
Mouren et al.	2021	France	65	1 (1/1)	1	P. jirovecii	30 days	Non-severe COVID-19	P. jirovecii pneumonia	Chronic lymphocytic leukemia	Histopathological examination and culture samples from affected areas	IV Liposomal amphotericin B (24/30) Oral Posaconazole (6/30) Surgical intervention (30/30)	Patient discharged
Niamatullah et al.	2023	Pakistan	59.4 ± 15.3	10 (7/3)	10	P. jirovecii	NR	Severe COVID-19: 8/10 Non-severe COVID-19: 2/10	P. jirovecii pneumonia	Hypertension: 5/10 Underlying malignancy: 3/10 Diabetes mellitus: 6/10	Clinical and radiological findings	IV Cotrimoxazole + IV Corticosteroids	Discharged: 6/10 Deceased: 4/10
Shabana et al.	2022	Egypt	62.47 ± 11.13	30 (13/17)	30	Mucor spp.	NR	NR	Orbital apex syndrome: 13/30 Ocular ischemic syndrome: 6/30 Orbital cellulitis: 4/30 Orbital cellulitis and Orbital apex syndrome: 3/30 Superior orbital fissure syndrome: 4/30	Diabetes mellitus: 27/30	Histopathological examination and culture samples from affected areas	NR	Discharged: 24/30 Deceased: 6/30
Singh et al.	2021	India	55	1 (1/0)	1	Aspergillus spp.	NR	NR	Invasive aspergillosis	Diabetes mellitus	Histopathological examination and culture samples from affected areas Histopathological examination, qPCR, and culture samples from affected areas	IV Amphotericin B	Patient discharged
Singh et al.	2021	India	55	1 (1/0)	1	Mucor spp.	NR	NR	Rhino-orbital mucormycosis	Diabetes mellitus		IV Amphotericin B	Patient discharged
Swain et al.	2022	India	45–55	2 (1/1)	2	Aspergillus spp.	1.5–2 months	Severe COVID-19: 2/2	Subacute invasive pulmonary aspergillosis: 1/2	Diabetes mellitus: 2/2	Histopathological examination and culture samples from affected areas Histopathological examination and culture samples from affected areas	Voriconazole (1/2)	Patients discharged: 2/2
Swain et al.	2022	India	45–55	2 (1/1)	2	Mucor spp.	1.5–2 months	Severe COVID-19: 2/2	Pulmonary mucormycosis: 1/2	Diabetes mellitus: 2/2		IV Liposomal amphotericin B + Surgical intervention (1/2)	Patients discharged: 2/2
Uttamchandani et al.	2022	India	27	1 (1/0)	1	Mucor spp.	NR	NR	Sinusitis and orbital cellulitis	Diabetes mellitus	qPCR, serum beta-d-glucan, and serum galactomannan	Surgical intervention	Patient discharged
Vijayasekhar et al.	2022	India	40–60	270 (NR/NR)	270	Mucor spp.	From 14 days to 2 months	NR	Sinusitis: 270/270 Cranial involvement: 61/270 Orbital involvement: 131/270 Cutaneous involvement: 6/270 Lung involvement: 3/270	Diabetes mellitus: 270/270	Histopathological examination and culture samples from affected areas	IV Amphotericin B + Oral Posaconazole (270/270) Surgical intervention (159/270)	NR
Zubair et al.	2021	Pakistan	71	1 (1/0)	1	P. jirovecii	20 days	Severe COVID-19	P. jirovecii pneumonia	Hypertension and diabetes mellitus	Histopathological examination, qPCR, and culture samples from affected areas	IV Cotrimoxazole + IV Corticosteroids	Patient discharged

Mean ± SD.

COVID-19, coronavirus disease-19; NR, not reported; qPCR, quantitative polymerase chain reaction.

Population characteristics

Among the 33 included studies, there was a total population of 774 participants, ranging from 21 to 87 years. Of these 746 developed a fungal infection. The country with the highest number of reported investigations was India (42.4%), followed by Pakistan (12.1%). Of the total participants, the majority (62.2%) were male, with only one study not reporting the gender of its participants. In 19 studies report the patient outcome; among these studies, a mortality of 14.1% is observed. All included studies were retrospective.

Regarding the risk of bias assessment, a total of 12 studies were classified as low risk of bias, while 21 studies were classified as having a high risk of bias (Supplemental Table S2).

Mucor spp. infection

In 19 studies, Mucor spp. was reported as the primary mycosis. India had the highest number of reported cases of Mucor infections (42.1%). The total number of reported patients was 711, with sinusitis being the most common disease (50%), followed by orbital infection (31.6%). The most common comorbidity was diabetes mellitus (88%). Clinical presentation of COVID-19 among patients who developed mucormycosis was reported in only five studies, with 40% developing severe COVID-19. The outcome is reported at the end of the follow-up in only 15 studies, which included a total of 372 patients. Of the total number of patients in these studies, 58 died (15.6%).

Pneumocystis jirovecii infection

In 10 studies, P. jirovecii was reported as the main mycosis. The places with the most reports of P. jirovecii infection were Pakistan (30%) followed by Spain (20%). The total population that developed P. jirovecii disease consisted of 28 patients aged between 45 and 82 years. The most reported comorbidity was hypertension, and seven patients died during the follow-up (15%).

Aspergillus spp. infection

In seven studies, Aspergillus spp. was reported as the primary mycosis. The total population across all the studies consisted of nine patients, with an age range of 41–74 years. The most common comorbidity was diabetes, and one patient died (11.1%) during follow-up.

Discussion

This is the first systematic review of studies that describe fungal infections in patients after recovering from COVID-19. In general, fungal infections in patients recovered from COVID-19 are less frequent than in the acute phase of the disease.⁵⁶ The majority of fungal infections in these patients occurred in men over 45 years of age with a history of COVID-19 severe illness (pneumonia severe with respiratory rate >30 breaths/min, or severe respiratory distress, or SpO₂ <90% on room air),⁵⁷ causing a mortality of 14%. Unlike fungal co-infections in patients with acute COVID-19, where the majority of pathogens reported were Candida (7.1%), Aspergillus spp. (4.6%), Mucor spp. (1.3%), and Cryptococcus (0.5%),^56,58 we observed that the most frequently reported fungal infections in patients recovered from COVID-19 were Mucor spp. and P. jirovecii.

One of the main risk factors for invasive fungal infections is the use of corticosteroids. Corticosteroids are usually indicated in patients with severe COVID-19 due to their association with reduced mortality and the need for MV.⁵⁹ However, it is known that they can act as immunosuppressants through (a) antagonism in the differentiation of macrophages and production of cytokines such as Interleukin 1 (IL-1), Interleukin 6 (IL-6), Tumor necrosis factor-alpha (TNF-α); (b) decreased production of proinflammatory factors such as prostaglandins and leukotrienes; (c) decreased of the adhesion and chemotaxis of neutrophils to endothelial cells; and (d) suppression of the lymphocyte population and secondary lymphopenia. All of these factors together predispose to the presentation of invasive fungal infections.⁶⁰ Corticosteroids as a treatment for COVID-19 can increase the risk of invasive fungal infection 3.33 times more than patients who do not receive corticosteroids.⁶¹

Mucormycosis is a rare angio-invasive fungal infection caused by fungi of the genus Rhizopus, of the order Mucorales, which has high lethality (40–60%). Its main risk factors are diabetes mellitus, therapy with systemic corticosteroids, and neutropenia.⁶² The majority of LC mucormycosis cases reported in our study came from India; a country that, already in the pre-COVID era, had the highest number of mucormycosis cases globally, showing a prevalence close to 80 times higher than in developed countries (0.14 per 1000 versus 0.005–1.7 cases per million inhabitants). Similarly, we observed that the most frequent comorbidity in Mucormycosis patients was diabetes mellitus, which was also the most frequently reported risk factor (57–93%), in patients with or without SARS-CoV-2 infection.^63,64 Another common factor between patients with mucormycosis and COVID-19 was the use of corticosteroids; its use rose to 88% of COVID-19 cases in a systematic review. Unfortunately, it was not possible to determine this proportion in our study. However, as most patients included in this study occurred in the second wave of COVID-19 and had a history of severe COVID-19, we presume that they received corticosteroids as part of their protocolized therapy. Likewise, as in patients with or without acute COVID-19 infection, the most frequent presentation of Mucormycosis was the sinus and rhino orbital forms.^65,66

Surprisingly, mortality from mucormycosis in LC was lower than that reported in the pre-COVID era, despite most of these co-infections occurring in the second wave of COVID-19, where the highest peak occurred. Of mortality worldwide, many countries like India suffered from the saturation of their health services with shortages of resources and medicines.⁶⁷ This observed better prognosis is likely secondary to differences in the pathogenesis of mucormycosis in COVID-19 than in non-COVID-19 patients. It is postulated that COVID-19 could have caused an increased risk of mucormycosis due to virus-induced endothelial dysfunction, hyperglycemia due to stress and corticosteroids, and hyperferritinemia caused by the hyperinflammatory response to the virus.⁶⁸ Likewise, COVID-19 has been associated with a dysregulated immune response with lymphopenia, which is secondary to the migration and sequestration of T lymphocytes in organs infected by SARS-CoV-2, mainly the lungs, and overactivation with subsequent depletion of T cells.^69–71 Both patients with mucormycosis with or without COVID-19 showed elevated activation and exhaustion of T lymphocytes. However, patients with non-COVID-19 mucormycosis showed greater exhaustion of CD4 HLADR, CD38, and LAG-3 T lymphocytes, which could explain the worse prognosis in this group of patients.⁷²

The second most frequently reported fungal microorganism in LC was P. jirovecii, which generally causes pneumonia in patients with HIV infection and CD4 T lymphocytes <200 cells/µl. Pneumocystis jirovecii pneumonia in LC usually occurs 18–180 days after SARS-CoV-2 infection. Most patients reported absolute lymphocyte count <0.5 × 10³ cells/µl and bilateral ground glassy interstitial infiltrates. Similar to what was observed with mucormycosis, mortality by P. jirovecii infections in LC HIV-negative was lower than HIV-negative patients without COVID-19.⁷³

Finally, the frequency of pulmonary aspergillosis in LC was shallow, contrary to what was observed in the acute phase of COVID-19, where it can be present in up to 34% of patients in the intensive care unit,⁷⁴ with a mortality of 50%⁷⁵; a number which is five times more than what was observed LC. Coronavirus disease-associated pulmonary aspergillosis is usually diagnosed an average of 10 days after the diagnosis of COVID-19, mainly in patients who were admitted to the intensive care unit due to Acute Respiratory Distress Syndrome and/or need for MV (97.8%). This higher prevalence of pulmonary Aspergillosis in the acute phase is probably due to its pathophysiology, since after SARS-CoV-2 infection, the affected pulmonary epithelial barrier creates an environment that facilitates invasion by Aspergillus in the pulmonary parenchyma.⁷⁶

Some limitations should be considered when interpreting the results of this systematic review. The main limitation was the impossibility of performing a meta-analysis, given that most of the studies comprised case reports. Likewise, there is a difference in the time to develop the fungal infection between the studies; in fact, some studies do not report it; this could mean that other variables (COVID variants, immunological parameters such as T-cell counts, immunization status, etc.) that could intervene in the development of the infection are not evaluated. Furthermore, it is not possible to discern between the occurrence of fungal infection in patients who suffered acute and prolonged COVID-19 disease. Therefore, it is likely there is underreporting of fungal disease in these patients due to the active search for these infections by clinicians. Moreover, another limitation is the heterogeneity inherent to the patient populations.

Conclusion

Fungal infections could become a significant public health problem in patients recovered from COVID-19. Patients’ clinical presentation and prognosis after recovering from COVID-19 with fungal infection differ from those reported patients with acute COVID-19 infection and those without COVID-19 infection.

Supplemental Material

sj-docx-1-tai-10.1177_20499361241242963 – Supplemental material for Fungal infections in patients after recovering from COVID-19: a systematic review

Supplemental material, sj-docx-1-tai-10.1177_20499361241242963 for Fungal infections in patients after recovering from COVID-19: a systematic review by Juan R. Ulloque-Badaracco, Cesar Copaja-Corzo, Enrique A. Hernandez-Bustamante, Juan C. Cabrera-Guzmán, Miguel A. Huayta-Cortez, Ximena L. Carballo-Tello, Rosa A. Seminario-Amez, Miguel Hueda-Zavaleta and Vicente A. Benites-Zapata in Therapeutic Advances in Infectious Disease

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Vicente A. Benites-Zapata

Supplemental material

Supplemental material for this article is available online.

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