diabetes mellitus may predispose individuals to invasive fungal infections ( ifi ) probably 
 related to impaired functions of neutrophils , macrophages , cellular and humoral immunity , 
 and iron metabolism ( 1 , 2 ) . children with type 1 diabetes ( t1d ) who present with ketoacidosis have 
 increased susceptibility to infections partly due to the acidic environment that is ideal 
 for certain pathogens including invasive fungi ( 1 , 
 3 ) .
majority of the ifis in children with poorly 
 controlled t1d and ketoacidosis are caused by zygomycoses and are invariably fatal without 
 aggressive management ( 4 ) .
the key to good outcome is 
 fast and accurate diagnosis which is usually difficult to establish due to non - specific 
 clinical symptoms and signs and the need for invasive diagnostic procedures for confirmation 
 of ifi ( 4 , 5 ) . 

the treatment is often challenging as it involves extensive surgical debridement of involved 
 tissues in addition to antifungal drugs ( 4 ) .
the 
 outcome is generally poor in resource constrained setups like ours but is gradually showing 
 improvements ( 6 , 7 ) .
the data on outcome of ifis in children with t1d is scarce and is almost 
 confined to invasive zygomycosis ( 4 ) . with an aim to 
 determine the clinical spectrum and final outcome of children diagnosed with t1d and ifi 
 over the last decade at our hospital , we performed a retrospective review of their medical 
 records .
the analysis of hospital data of patients with t1d diagnosed to have a confirmed ifi was 
 conducted at advanced pediatrics center of our institute which is a tertiary care referral 
 center located in northwest india and included the period from march , 2004 to february , 
 2014 .
all patients were diagnosed as t1d according to the international society for 
 pediatric and adolescent diabetes ( ispad ) criteria published in 2000 and revised in 2009 
 ( 8 , 9 ) .
the 
 diagnosis of associated fungal infection was based on microbiological and/or 
 histopatholgical examination of tissue specimens .
data related to the basic demographic 
 profile , age at the time of diagnosis , mode of initial presentation like diabetic 
 ketoacidosis ( dka ) , imaging details , treatment modalities , duration of hospitalization and 
 the final outcome were noted .
ten patients ( 6 girls and 4 boys ) amongst 524 children with t1d on follow up in pediatric 
 diabetes clinic were treated for various ifis during the study period .
the mean ( sd ) age of 
 presentation was 9.1 ( 3.4 ) yrs ( range 312 yrs ) .
the predisposing factors included poor adherence to insulin 
 therapy resulting in poor metabolic control ( mean hba1c 9.3  1.2% ) and presence of acidosis 
 in 9 patients and malnourished state in all ( mean bmi 12.6  1.2 kg / m ) .
nine patients presented with dka . the commonest presenting 
 feature related to fungal infection with suspected rhinocerebral involvement was facial 
 and/or orbital swelling in 5 patients , followed by serosanguineous nasal discharge and 
 ophthalamoplegia .
the most common site of fungal 
 infection was nasal cavity and paranasal sinuses seen in 6 patients ; 5 of these were due to 
 mucormycosis while 1 had aspergillus flavus .
sinusitis involved ethmoid sinus in 5 patients 
 and maxillary and frontal sinuses in 4 patients each ( table 1table 1clinical and 
 laboratory profiles , treatment modalities and outcome of the study 
 cohort ) .
lung involvement was seen in 5 patients ; 2 of these 
 had pleural and thymic involvement in addition .
all patients 
 showed neutrophilic leucocytosis with mean leukocyte count of 12.3  10/l . 

radiological investigations included contrast enhanced computed tomography ( cect ) scans of 
 suspected involved sites in all patients .
1.a : soft 
 tissue opacities in frontal and ethmoid sinuses with blocked osteomeatal complex .
b : 
 opacification of right maxillary sinus . ) ; 2 of these had orbital extension . 

2.a & b : cect chest 
 showing cavitatory pneumonia on right side . ) ; 1 patient , described elsewhere , showed 
 empyema in addition ( 10 ) .
another patient had 
 necrotic thick walled abscess in the thymus with consolidation of apical segment of right 
 upper lobe and small subpleural nodular lesions in the right lower lobe ( 11 ) .
a : soft 
 tissue opacities in frontal and ethmoid sinuses with blocked osteomeatal complex .
confirmation of diagnosis by direct microscopy of specimen ( smear / aspirate ) was made in 1 
 patient , by histopathological examination in 5 patients and by both techniques in 4 
 patients .
culture on sabouraud dextrose agar grew rhizopus microsporum ( rhizopodiformis ) in 
 1 patient .
the most common yield was from smear or histopathological examination of tissues 
 obtained at the time of surgical debridement of paranasal sinuses . in 2 patients who had 
 serosanguineous nasal discharge
the 
 identified etiological fungi belonged to the order mucorales in 9 cases ( 1 further 
 identified as rhizopus microsporum ) and aspergillus flavus in 1 patient .
the mean time from 
 presentation to diagnosis was 5.8  4.7 days ( range 114 days ) .
all patients were treated with either intravenous amphotericin b ( conventional or 
 liposomal ) or voriconazole for a targeted duration of 46 weeks .
surgical intervention was 
 done in 8 patients and included debridement of paranasal sinuses by either endoscopy or 
 external approach in 5 , excision of brain abscesses in 1 , resection of affected lung areas 
 in 2 and excision of thymic abscess in 1 patient .
mean duration of hospital stay was 41.7 
  27.2 days ( range 290 days ) .
two out of 10 patients died ; 1 with pulmonary mucormycosis 
 suffered massive hemoptysis on day 14 of hospitalization while the other with disseminated 
 aspergillosis died of a large bout of hematemesis and showed an intestinal perforation on 
 autopsy .
all survived children have remained well over a mean duration of 4.96  3.3 yrs 
 ( range 9 mo9 yrs ) in follow up except 1 who continues to show mild restrictive pattern on 
 pulmonary function tests .
invasive mycoses are uncommon but often lethal infections that disproportionately affect 
 t1d patients with poor metabolic control ( 2 , 3 ) .
poor adherence to insulin therapy , malnourished state 
 and episodes of ketoacidosis particularly predispose children with t1d to develop ifis 
 ( 2 , 3 , 11 , 12 ) .
majority 
 of our patients had all these critical factors required for development of ifis .
poor 
 glycemic control may result in dysfunctions of macrophage phagocytosis , neutrophil 
 chemotaxis and oxidative killing ( 1 ) , and ketoacidosis 
 may induce a temporary block in binding of iron to transferrin providing free iron which 
 enhances growth of many ifis particularly mucormycosis ( 2 , 13 , 14 ) .
poor compliance to therapy as evidenced by poor clinic attendance , risk 
 taking behaviors and recurrent admissions for dka has been documented to increase 
 susceptibility to ifis ( 12 ) .
similarly malnourished 
 state resulting either from a poor glycemic control or poor dietary management predispose 
 diabetic children to ifis ( 3 , 10,11,12 ) .
the presence of critical predisposing factors and an unusually high 
 occurrence of ifis in our patients is probably a result of the prevailing healthcare 
 situation related to the management of t1d in children in our setup ( 15 ) .
late diagnosis of diabetes due to lack of awareness of parents and 
 the primary healthcare physicians is common in india ( 15 ) .
poor metabolic control is also common due to 
 lack of comprehensive diabetes care ( 15 , 17 ) .
there are only a few specialized centers and 
 majority of the patients are treated by the primary care physicians who have limited 
 knowledge about the disease and the modern treatment options ( 15 ) .
additionally , poor socioeconomic status often makes even the 
 conventional insulin therapy and blood glucose monitoring unaffordable by the parents ( 15 ) .
the prevention of ifis in children with t1d requires 
 early diagnosis of diabetes before onset of ketoacidosis , meticulous glycemic control in 
 follow up and good nutritional management .
improvements in diagnosis and care of children 
 with t1d in our country setup will probably lower the incidence of ifis in these patients in 
 future .
establishment of an early diagnosis of ifi is important but is often difficult due to 
 absence of specific symptoms ( 5 ) .
we believe that a 
 high index of clinical suspicion in a setting of predisposing risk factors present in our 
 patients resulted in rapid establishment of diagnosis .
presence of subtle clinical features 
 like dry cough , tachypnea persisting after resolution of acidosis , facial swelling , 
 serosanguineous nasal discharge and low grade fever in poorly controlled , malnourished 
 children who present in ketoacidosis are pointers to the presence of ifis ( 5 , 11 , 12 ) . in patients
suspected to have rhinocerebral 
 involvement , smear examination of scrapings from nasal or sinus cavity are useful aid to 
 rapid diagnosis .
the diagnosis of pulmonary ifi is highly probable if the ct scan shows 
 cavitary pneumonia in a child with minimal pulmonary symptoms and previously described risk 
 factors ( 10 ) .
fine needle aspiration cytology can be 
 very useful in reaching an early diagnosis of pulmonary ifis as compared to more invasive 
 transbronchial biopsy ( 10 , 18 ) .
the cornerstone of management is a combination of antifungal drugs and early surgical 
 debridement of involved tissues that may prevent extension of infection to the surrounding 
 areas ( 4 , 19 ) . 

treatment with antifungals alone is usually ineffective due to poor concentrations in 
 affected tissues resulting from vascular invasion , thrombosis , occlusion and infarction 
 ( 4 ) . in our patients who had rhinosinusitis ,
early 
 surgical debridement probably prevented a contiguous extension of infection into the brain . 

one 
 of the 2 patients who received only antifungal therapy died ; the survivor received liposomal 
 amphotericin b which had been previously reported to be able to achieve cure even in the 
 absence of associated surgery ( 20 ) .
the success rates 
 of a multimodal treatment approach in our study are similar to those achieved across many 
 centers around the world ( 4 , 5 , 19 ) .
the long term morbidity 
 related to consequences of the fungal disease was also minimal and confined to the sequelae 
 of tissue loss from radical surgeries . in conclusion ,
rapid and accurate diagnosis of ifis in children with t1d and a multimodal 
 management approach involving early surgery , appropriate antifungal therapy and control of 
 hyperglycemic state is successful in achieving a good outcome . to the best of our knowledge , 

ours is the largest single center data and the first study from a developing country setup 
 on ifis exclusively in children with t1d .
 abstractthere is scarcity of data on spectrum and outcome of invasive filamentous fungal 
 infections ( ifis ) in children with type 1 diabetes ( t1d ) from developing countries . 
 a 
 retrospective review of medical records of children with t1d hospitalized with ifi over 
 the past decade at the pediatric endocrinology and diabetes unit of a large tertiary care 
 hospital of north india was performed with an aim to study their clinical spectrum , 
 hospital course and final outcome . 
 of the 10 patients studied , nasal / paranasal involvement 
 was seen in 6 and pulmonary involvement in 5 patients . one patient developed disseminated 
 disease . 
 majority of the identified mycoses belonged to class zygomycetes order mucorales . 
 
 early surgery along with antifungal therapy helped limit the extension of infection and 
 achieve a good outcome in majority of patients . 
 two patients died ; one with a late 
 diagnosis of pulmonary mucormycosis and the other with disseminated disease . 
 the longterm 
 morbidity in the survivors was minimal . in conclusion , 
 rapid diagnosis followed by a 
 multimodal approach involving aggressive surgical debridement , appropriate antifungal 
 therapy and control of hyperglycemic state is the key to good outcome in this otherwise 
 lethal infection . 