INVASIVE FUNGAL

INFECTIONS
DR MAKTEP YADANG
DEPARTMENT OF MEDICAL MICROBIOLOGY
 Learning objectives
By the end of this module, we should be able to
• Define invasive fungal infections (IFIs)
• Explain the epidemiology of invasive fungal infections
• Explain the risk factors
• Identify clinical features of IFIs
 Outline
• Overview
• Epidemiology
• Risk factors
• Clinical features
 Invasive Fungal Infections – Overview
• Generally used exclusively to characterize a systemic, generalized, deep
seated, visceral and life threatening fungal infection rather than
superficial, localized benign and self limiting disease.

• This term is however confusing and misleading. Fungal infections are by

nature ‘invasive’ but difficult to differentiate between mild moderate and
severe infection.
 Overview
• Infectious fungal diseases are major cause morbidity and mortality
• About 300 out of over 100,000 species of fungi cause diseases in human.
• Yearly, an estimated 2million people are infected with Candida,
Aspergillus, Cryptococcus and Pneumocystis
• These are the most common fungi organism
• Over 90% of fungi related deaths are attributed to the above fungi
 Overview
• IFI are largely neglected globally in spite of the burden
• There is lack of data, paucity of national surveillance programmes
• Incidence is likely to be underestimated despite the increasing trend of IFI
• Most patients affected are those immunocompromised,
immunocompetent, critically ill, recipients of transplanted organs,
haemato-oncological patients and those with prolonged steroid use etc.
 Overview of IFIs –Risk factors
• Congenital
• Defective IL-10 synthesis
• Mannose binding lectin deficiency
• Polymorphisms of toll-like receptors
• Acquired
• Exposure to high concentration of fungal spores
• Prolonged neutropenia
• Recent major surgery: recurrent GI perforation, anastomotic leak
• Central venous catheter
• Corticosteroid
• Haemodialysis
• Parenteral nutrition
• Necrotising pancreatitis
• Treatment with agents that impair cellular immunity e.g. steroids, purine analogue eg fludarabine
• Monoclonal antibodies to lymphocytes e.g. anti-CD20
• Diagnosis of IFI is challenging and their timely treatment depends on high
index of suspicion.
• Clinical features are non-specific and current diagnosis lack sensitivity
and specificity.
• IFIs are identified by the presence of mould or yeast in deep tissue biopsy
or culture obtained by sterile procedure.
•
 OVERVIEW
The four most common IFIs are
• Invasive Candidiasis
• Invasive aspergillosis
• Cryptococcosis
• Pneumocystis
 Invasive Candidiasis
• Candida is the most common cause of invasive fungal infection in the world
• It is a normal commensal found on the skin, in the oral cavity, female genital
tract, gastrointestinal tract.
• Up to 70% of healthy people above one year of age are colonized by candida
• Invasive candidiasis arises form the patients own flora
• Introduced into the blood stream or deep tissues following iatrogenic break of
skin and mucosal barrier
 Invasive candida
• It is predominantly a disease of the critically ill or hospitalized patient
• Candida albicans: 65% blood stream isolate – dominant specie
• Candida glabrata: 15% (poses greatest treatment challenge)
• Candida tripicalis 6%
• Candida parapsilosis 5% (2nd most common in SE, America and Asia)
• Candida krusei 2%
 Invasive candida
• Epidemiology
• Incidence rate varies geographically but it is on the rise 1.2% to 2.1% between 2001 and 2006. .
• In Europe it make up 2-3% of all nosocomial infections (4 times < in the USA)
• In Europeean surveillance incidence is 0.59/10000 population and 11/10000 admissions
• In intensive car unit incident rate was 5-10 time higher than patients in medical or surgical
wards
• Average mortality rate for candidaemia is 43%. This is higher for any other blood stream
infection.
• Candida chorioretinitis found in 8-16% of candidaemic patients
 Invasive candida
• Candidaemia is the most common manifestation
• Candidaemia may go unnoticed when it produces a single febrile peak
among many –typically critically ill patient
• Septic shock may be indistinguishable from bacteria infection
• Persistent fever and clinical deterioration may be a sign of intraabdominal
candidiasis
 Invasive candidiasis
• Clinical features: largely non-specific
• Chronic mucocutanous: disfiguring lesions of the face, scalp, hand and nails,
occasional thrush and vitiligo
• Oropharyngeal candidiasis: sore and painful mouth, burning mouth or
tongue, dysphagia, thick white patches in the oral cavity
• Oesophageal Candidiasis: normal is half of patients, dysphagia,
odynophagia, retrosternal pain, epigastric pain, nausea and vomiting
• `23469
 Invasive candidiasis
• Non- oesophageal: epigastric pain abdominal pain fever and chills, abdominal mass (in some
cases)

• Genitourinary:
• VVC- erythematous vagina and labia; a thick curdlike discharge, normal cervix on speculum.
• Candida cystitis: asymptomatic in many, frequency, urgency, dysuria, haematuria, suprapubic pain
• Asymptomatic candiduria: most catheterized patients are asymptomatic
• Ascending pyelonephritis: flank pain, abdominal cramps, nausea, vomiting, chills and haematuria
• Fungal balls: intermittent urinary tract obstruction with subsequent anuria, renal insufficiency
 Invasive aspergillosis
• Aspergillosis is the most common mould infection in humans
• Accounts for the 85% of invasive mould disease
• Aspergillus is found in soil, decaying vegetation, food, air and water supply.
• Its ubiquitous spores reach the respiratory tract by inhalation
• In immunocompromised host, it results in invasive pulmonary aspergillosis
(IPA)
• It can be disseminated in late disease to the brain and kidneys
 Invasive aspergillosis
• Epidemiology
• Estimated yearly cases worldwide are 200,000
• About 50% of all IA are found in patients with haematological malignancy, mostly AML, ALL and
recipient of allogenic HSCT
• Prolong severe neutropenia (<500cell/mm3; >10days) is the single most important risk factors for IA
• Mortality rates of haematological patients with IA is large clinical trials reached 29% at 3 months.
• Commonly found in SOT recipient – heart and lung
• Dominant risk factor is the due to impairment by immunosuppressant drugs.
• ICU patients are the second largest at risk population for AI
 Invasive aspergillosis
• Reported incidence rates are variable but generally high 6.1-57/1000 ICU admissions)
• Critically ill patients have high mortality rates ranging from 46 to 80% and 90% in those
with cerebral involvement at 4 months
• Associated with concomitant viral respiratory infections due to H1N1 influenza,
adenovirus and cytomegalovirus
• Infection in transplant recipient leads to greater immunosuppressive effect
• Genetic factors have been associated with increased risk of such as toll-like receptors -4
(TLR4) haplotypes and pentraxin 3 (PTX3) deficiency. Despite a large number of people
at risk only a minority eventually develop IA.
 Invasive aspergillosis
• Clinical presentation – non specific, similar to IC.
• Fever, Cough, dyspnoea, Pleuritic chest pain, haemoptysis in prolonged neutropenia or
immunosuppression
• In neutropenic patients, fever unresponsive to bread-spectrum antibiotics is often an early
sign
• Cough or chest pain with or without haemoptysis – signs of pulmonary infarction due to
mould-induced vascular obstruction
• Refractory fever and deteriorating lung function – mechanically ventilated ICU patients
• Lung consolidation
 Invasive aspergillosis
• Rapid progressive worsening Hypoxemia
• Seizure or focal neurologic signs – late manifestation of cerebral
dissemination
• Respiratory failure and death
• Primary extra pulmonary organ manifestation is rare.
• Disseminate to the CNS, Kidney, heart causing MODS
 Cryptococcus
• Epidemiology
• More than 1 million cases with about 650, 000 deaths annually
• Principal sites of infection are the CNS, lungs, disseminated disease
• Most fatal fungal disease worldwide
• Most common disease manifestation is cryptococcal meningitis - principally in HIV infected patients
with CD4 <400cells/ul or iatrogenically immunosuppressed
• The dominant specie in this yeast is Cryptococcus neoformance - ubiquitous
• Annual incidence rate in SSA ranges between 100 to 4000 per 100,000 among HIV positive.
• Life long Latent infection occurs after inhalation of the yeast
 Cryptococcus
• Globally, HIV is the leading risk factor for CM
• Other risk factors are prolonged steroid use, malignancy, transplantation
• There is widespread decline in HIV-associated CM.
• CM is now seen in approx. 2.8% of all SOT recipient – largely kidney transplant recipients
• 3rd most common invasive fungal infection post transplant period
• Infection occur mostly >18 months after transplantation
• Rarely seen in immunocompetent hosts
• Immunocompetent patients are more likely to have pulmonary disease and less likely to develop CM
• Lung and skin are predominantly affected.
 Cryptococcus
Clinical features: Non-specific
• Pulmonary cryptococcosis:
• Fever, malaise, cough with scant sputum, pleutitic chest pain, haemoptysis (rare), ARDS
• Rales and pleural rubs are unusual findings.
• Pulmonary effusion may be present but uncommon.
• Calcification and pulmonary fibrosis are usually absent.
• Ranges from minimal to severe with headache, malaise, fever, visible disturbances, nausea and vomiting
• Meningism is rare unlike in bacterial meningitis
• Night sweats are uncommon but occur with CNS or disseminated disease
• CNS Cryptococcosis:
• Meningitis and meningoencephalitis are the most common manifestation
• Usually subacute or chronic in nature
• Fatal without treatment as death may occur within 2 weeks with onset of symptoms
• Headache, altered mental status including personality changes, confusion, lethargy,
obtundation and coma
• Nausea and vomiting are often associated with increased ICP
• Fever and neck stiffness are less common
• Blurring of vision, photophobia, diplopia may result from arachnoditis,
papilloedema, optic nerve neuritis or chorioretinitis
• Other are hearing defects, seizures (in advance disease), ataxia, aphasia,
choreoathethoid movements
• Dementia is a potential sequelae and may indicate the presence of
hydrocephalus as a late complication
• Cryptococcosis in other sites
• Disseminated sites include skin, prostate and medullary cavity of bones
• Cutanous manifestation: papules, pustules, ulcers and draining sinuses
• Umbilicated papules may resemble molluscum contagiosum
• Cellulitis with necrotizing vasculitis occur in those with organ transplantation
• Bone lesion occur in 5-10% of patients and are usually osteolytic or resemble
cold abscesses and may be confused with TB or neoplasm
• Other less common forms
• Myocarditis
• Chorioretinitis
• Hepatitis
• Renal abscess
• Prostatitis
• Myositis
• Adrenal involvement
 Cryptococcus
• Skin lesions predominantly occur in immunocompetent patients, may
present as pustules papules, ulcer, cellulitis, superficial granulomas or
abscesses
 Pneumocystis Jeroveci Pnuemonia (PJP)
• Formally known as pneumocystis carini pneumonia (PCP)
• Most common opportunistic infection in persons with HIV
• Officially classified as a fungal pneumonia, PJP does not respond to
antifungals
• It is found in 3 distinct morphologic stages: trophozoite (trophic form),
sporozoite (precystic form), the cyst (spores)
• Prevelence of 88% in lung cancer patients
 PJP
• Rare in solid – organ transplant because of prophylaxis
• Prior to use of HAART, PJP occurred in 70-80% of HIV patients and
frequency decreases with use of prophylaxis
• HIV patients are more prone to PJP than those who are seronegative.
• Increasing infections in Africa
• In SSA, TB is a common co-infection in persons with PJP
 PJP
• Mortality rate currently is about 10-20%
• Prognosis is worse in in persons without HIV infection, those with
concurrent pulmonary disease, pneumothorax, those who require
mechanical ventilation due to delayed diagnosis and initiation of
appropriate treatment.
• Prevention: Ceassation of smaoking, chemoprophylaxis in patients with
HIV infection and those without HIV
 PJP
• Symptoms are non-specific
• It runs a more subacute indolent course and tends to present much later often after several
weeks of symptoms
• Progressive exertional dyspnoea
• Fever and chills
• Non productive cough
• Chest pain/discomfort
• Weight loss
• Haemoptysis (rare)
 PJP
• Physical examination: Non-specific but could be normal in 50% of
patients
• Tachypnoea
• Febrile
• Tarchycardia
• Mild crackles and rhonchi
• Cyanosis, nasal flaring and intercostal recession in children
 PJP
• Extrapulmonary manifestation
• Although rare, may present in almost any organ system
• CNS
• Bone marrow (may have necrosis with resultant pancytopenia)
• Lymphadenopathy
• Retinal cotton wool spot in the eyes
• Rapidly enlarging thyroid mass
• GIT
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