ABSTRACT

Fungi are ubiquitous microbes and form a fraction of the symbiotic human microbiome. Transition from normal commensals to opportunistic mycoses can occur in immunocompromised hosts. Endemic mycoses are caused by fungi that are acquired from environmental sources. Fungal infections can be classified based on the depth of tissue invasion. Superficial diseases are limited to skin, nails, and mucous membrane while systemic dissemination can affect multiple organs including endocrine glands. Fungal involvement of the adrenals, pituitary, thyroid, pancreas, and gonads is well recognized. On the other hand, individual with diabetes mellitus and Cushing’s syndrome are susceptible to fungal disease as a result of immune dysfunction. Mucormycosis, candidiasis, and dermatophytosis occur more commonly in diabetes. Exogenous as well as endogenous Cushing’s syndrome is another endocrine disorder that predisposes to systemic fungal diseases. High index of suspicion is necessary to recognise these infections as clinical manifestations can be masked due to the anti-inflammatory properties of glucocorticoids. Autoimmune polyendocrine syndrome type I (APS-1) is a unique genetic disease where autoimmune damage predisposes to chronic mucocutaneous candidiasis (CMC) and a multitude of endocrine anomalies. Antifungal agents like azoles and polyenes can adversely affect the normal functioning of various endocrine pathways. Errors in diagnosis and treatment of the fungal infections of the endocrine glands can be critical. Equally important is to identify the various fungal diseases occurring in diabetes and other endocrine disorders. Conditions that predispose to fungal diseases such as diabetes and immunosuppressed states in organ-transplant recipients are becoming increasingly prevalent. Understanding of the critical interplay between the endocrine system and fungal pathogens are imperative for optimal patient outcomes in modern medicine.

INTRODUCTION

Fungi are classified as a separate kingdom that consists of single-celled or complex multicellular organisms. They are heterotrophs and unlike autotrophic plants, fungi lack chlorophyll and cannot synthesize their own food. They acquire nutrients from the surrounding media by osmosis.

Fungi are ubiquitous, transient, or persistent human colonizers which form the fungal microbiota or mycobiome. The human microbiota consists of a diverse array of microorganisms such as viruses, bacteria, fungi, protozoa, and parasites that reside in and around the human body. Fungi comprise ≤0.1% of the total human microbiota, but it still plays a crucial role in human health and disease (1).

Fungal species have complex interactions with the human host, which can be viewed as a spectrum of symbiotic relationships. The association can be mutualistic where it is advantageous to both, or commensal where only one profits but the other is unharmed.  On the other hand, the connection can be parasitic where the fungi are benefitted with a damaging effect on the human host, or amensalistic where one organism is harmed but the other remains unaffected. These human fungal symbionts can transition from commensalism to parasitism within the body. Immune dysfunction is one of the common factors that influence this conversion. Endocrine diseases like diabetes mellitus, Cushing’s syndrome, and autoimmune polyglandular syndrome type 1 (APS1) are prone to fungal infections due to immune dysfunction.

The prevalence of superficial fungal infection is 20-25% (2). On the other hand, fungal infections tend to spread in individuals with low immunity such as patients with cancer or acquired immunodeficiency syndrome (AIDS) and recipients of immunosuppressive drugs. The reported incidence of invasive fungal disease is 5.9 cases per thousand per year (3). The dissemination may affect various endocrine glands leading to their dysfunction, the adrenal gland being the one most commonly involved. Endocrine system involvement in fungal infections would extend to the adverse effect of various antifungal therapy too. Azoles are the most frequently described class affecting the endocrine system and, adrenal glands and gonads are their primary targets.

The diverse aspects of this complex relationship between fungi and the endocrine system are described in this chapter.

TYPES OF FUNGAL INFECTION

Fungal infections have been classified based on both anatomic location and epidemiology. They can also be classified on the basis of morphological structure of the fungus.

Anatomical Categories

MUCOCUTANEOUS INFECTIONS

Mucocutaneous infections is a heterogeneous group characterized by infections of the skin, mucous membranes, and the nails. These infections are confined to the cutaneous surface, with little propensity for systemic dissemination. The effect can vary from mild to severe depending on the extent of involvement but are rarely fatal.

DEEP ORGAN INFECTIONS

Fungal infections can sometimes cause deep tissue involvement and have the potential for hematogenous and systemic spread. Dissemination of fungal infections is usually observed in immunocompromised conditions. If untreated, deep organ or systemic fungal affection can be fatal.

Epidemiological Categories

ENDEMIC MYCOSES

Endemic mycoses include infections caused by fungi that do not belong to the normal human microbiota but rather are acquired from environmental sources. In endemic mycosis, deep organ infection is almost exclusively caused by inhalation, whereas cutaneous disease is most often caused by direct contact with soil but can also occasionally result from hematogenous dissemination. Dermatophytid fungi are mainly acquired by environmental contact however, human-to-human transmission has been reported. Examples of endemic mycoses include coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, blastomycosis, penicilliosis, phaeohyphomycosis, sporotrichosis, and adiaspiromycosis.

OPPORTUNISTIC MYCOSES

Opportunistic fungi can be normal human microbiota components, but in the immunocompromised state, these organism transition from harmless commensals to invasive pathogens. These fungi invade the host from the usual sites of colonization, typically the mucous membranes or the gastrointestinal tract. Typical examples are candidiasis, aspergillosis, mucormycosis (zygomycosis), cryptococcosis, scedosporiosis, trichosporonosis, fusariosis, and pneumocystosis. Fungi that are reported to affect the various endocrine glands are shown in table 1.

Based on Morphology

YEASTS

Yeast are found as single rounded cells or as budding organisms. Examples are Saccharomyces cerevisiae, Candida albicans, and Leucosporidium frigidum.

MOLDS

Molds grow in filamentous forms called hyphae both at room temperature and in invaded tissue. The common molds are aspergillus (A. fumigatus, A flavus, and A brasiliensis), penicillium and rhizopus.

DIMORPHIC

Dimorphic fungi grow as yeasts or large spherical structures in the tissue but as filamentous forms at room temperature in the environment. These include histoplasma (H. capsulatum), blastomyces (B. dermatitidis), paracoccidioides (P. brasiliensis), coccidioides (C. immitis), penicillium (P. marneffei), and sporothrix (S schenckii).

Figure 1. Classification of Fungal Infections

FUNGAL DISEASES OF MAJOR ENDOCRINE GLANDS

Fungal infections are more prevalent in the immunocompromised state (table 2). There is a tendency for fungal infections to disseminate in such cases and affect endocrine organs like the pituitary, thyroid, parathyroid, pancreas, adrenal glands, and gonads. The involvement of these endocrine glands may lead to deficient hormone secretion. The clinical manifestations, diagnosis, and management of fungal infection of the major endocrine glands are discussed below.

Pituitary Fungal Infections

ETIOLOGY

Pituitary infections or abscesses are rare and account for less than 1% of pituitary lesions (4). Even among them, fungal infections are extremely unusual and occur predominantly in immunocompromised states. The mode of spread could be hematogenous, extension from adjacent structures like meninges, sphenoid sinus, cavernous sinus, and skull base, or iatrogenic during transsphenoidal procedures. Fungal infection of the pituitary can occur in the presence of underlying lesions like pituitary adenoma, Rathke’s cleft cyst, etc. Cushing’s syndrome, resulting from an adrenocorticotrophic hormone (ACTH) secreting pituitary adenoma, itself causes immunosuppression and further predisposes to fungal disease (5). Aspergillus is the most frequently reported fungal infection of the pituitary (6–8). Other fungi described to infect the pituitary include candida (9,10), Pneumocystis jirovecii (in HIV/AIDS) (11,12), and coccidia (13). In a review of 13 cases of pituitary aspergillus infection, five were immunosuppressed (14).

CLINICAL FEATURES

The clinical presentation of fungal infection of the pituitary can be variable (table 3).  Symptoms from mass effects such as headache, visual disturbances (due to optic chiasma compression), and ophthalmoplegia are the usual presenting features. Features suggestive of infection, such as fever, leukocytosis, and meningismus were absent in most of the reported cases (8,15,16). Aspergillus is known to cause angioinvasion and vasculitis, and thus can be additionally associated with features arising from cerebrovascular infarcts (8,14). Pituitary insufficiency can acutely manifest as hypotension and shock primarily from secondary hypoadrenalism (9). Gonadotrophin and other hormone secretion can be affected as a delayed sequalae,  but such reports are very rare (17). Pituitary stalk compression can induce hyperprolactinemia (18). Diabetes insipidus (DI) occur more frequently than seen with pituitary adenomas (10).

CAD – coronary artery disease, AHA – autoimmune hemolytic anemia, ICA – internal carotid artery, MCA – middle cerebral artery, ACA – anterior cerebral artery, DM – diabetes mellitus, MRI – magnetic resonance imaging

DIAGNOSIS

Fungal pituitary infections usually present with symptoms of headache, visual disturbance, and ophthalmoplegia and are often misdiagnosed as tumors (14). Identification of a mass in the sellar region in an immunocompromised state should raise suspicion of fungal etiology.  T1-weighted magnetic resonance imaging (MRI) of fungal abscess of pituitary shows nonspecific isointensity or hypointensity (4). Pituitary abscess of any etiology including fungal may demonstrate peripheral rim enhancement and calcifications on T2-weighted images. Low signals due to iron deposition are however indicative of fungal involvement (19). Involvement of the adjacent sinuses is another pointer for fungal disease (15,16). It is difficult to distinguish fungal pituitary infections from intrasellar bacterial infections and tumors, and the diagnosis is often confirmed during surgery or autopsy. Histopathological examination can reveal hyphae and fungal spores. Silver impregnation stains such as Grocott or Gomori methenamine silver, fungal culture, or fungal polymerase chain reaction (PCR) can confirm the diagnosis (4). Serum 1,3-β-D-glucan is positive in a broad range of invasive fungal infections, including candida (19). Serum galactomannan is however, a specific marker for invasive aspergillosis (20).

TREATMENT

Treatment includes antifungal therapy and drainage of the abscess by transsphenoidal endoscopic approach (14). Craniotomy is discouraged due to fear of intracranial dissemination. Deficiency of pituitary hormones may necessitate replacement (9). Voriconazole is the preferred therapeutic agent for aspergillus infection. Other medical options are liposomal amphotericin B, posaconazole, isavuconazole, and echinocandins (21). The recommended dose of voriconazole for central nervous system (CNS) aspergillosis is intravenous loading with 6 mg/kg every 12 hour for two doses followed by 4 mg /kg every 12 hour. The oral loading dose is 400 mg every 12 hour for two doses, followed by 200 mg twice daily (22). Oral treatment may be required for months. The exact duration of therapy is not established and depends on the clinical parameters. Antifungal therapy for other varieties of fungus should be administered as per standard practice. Mortality rates are high in disseminated disease with vascular invasion, immunosuppressed state, and in cases of a delayed diagnosis (14).

Thyroid Disorders

ETIOLOGY

Infections of the thyroid are rare as its rich blood supply, iodine content, and capsule are protective against microbial invasion (23). Fungi form a small subset among the microbial pathogens infecting the thyroid. A. fumigatus is the predominant fungi in general, whereas P. jirovecii is the most common cause of fungal thyroiditis in patients with AIDS (24,25). Table 4 enumerates the fungal infections reported to infect the thyroid. These infections are primarily seen in immunocompromised patients and usually is a part of disseminated infection. Both hematogenous and lymphatic spread can occur.  Direct invasion of the thyroid by fungal infection is also reported. Mycotoxin secreted by the fungus may affect thyroid function, however the evidence in humans is not definitive (26).

AML – acute myeloid leukemia, ALL – acute lymphoblastic leukemia, MDS – myelodysplastic syndrome, NHL- Non-Hodgkin’s Lymphoma, SLE- systemic lupus erythematosus, AIDS – acquired immunodeficiency syndrome, MNG – multinodular goiter, PAN – polyarteritis nodosa

CLINICAL FEATURES

Fungal infection of the thyroid usually occurs in presence of underlying critical illness. The symptoms of thyroid infection can get masked by the primary disease. Thyroid involvement can be often detected post-mortem in cases of disseminated fungal disease (42). Common clinical presentations include pain, swelling of the thyroid gland, and fever, often mimicking subacute thyroiditis. In severe cases, thyroid enlargement may cause dysphagia and respiratory distress due to esophageal and tracheal obstruction, respectively (25,42,43). Fungal thyroiditis typically follows the course of a brief phase of thyrotoxicosis followed by hypothyroidism. Recovery of thyroid function generally takes place in weeks to months. Sick euthyroid syndrome, which sometimes occurs in disseminated fungal infections, may confound thyroid function testing. The clinical presentation of different varieties of fungal infections is similar.

Aspergillus

A review of 28 cases of aspergillus thyroiditis by Tan et al. revealed that 12 (43%) patients had a primary thyroid infection. The rest had aspergillus infection elsewhere (usually lungs and airways). Fever, dyspnea, and neck swelling were the usual presentation. Dysphagia and airway obstruction resulted from mass effect and was fatal in two cases. The overall mortality rate was high (64%) (24).

Pneumocystis

Zavascki et al. described 15 cases of P. jirovecii thyroiditis. Most of the cases were reported in individuals with AIDS. It should be suspected if neck pain and swelling occur in presence of a CD4 count < 200/µL. Compressive symptoms such as odynophagia, dysphagia, dysarthria, and hoarseness have been reported. Extra-thyroid disease was present in 53% (8/15) of cases and documented usually on post-mortem studies. Most of the cases were euthyroid, three were hypothyroid, and one developed transient thyrotoxicosis (25).

Others

There are reports of infection of the thyroid with candida, histoplasma, coccidiodes, and, paracoccidiodes in immunocompromised hosts (37–41). The different varieties of fungal thyroiditis are clinically indistinguishable from each other.

DIAGNOSIS

Thyroid infection should be suspected in immunocompromised hosts who present with swelling and pain in the region of the thyroid gland. The thyroid involvement not uncommonly remains asymptomatic and gets detected post-mortem (42). Imaging of the neck by ultrasonography can be useful to define the morphology of the lesion. Computed tomography of the chest additionally identifies fungal lesions in the lungs, the usual site of primary or secondary infection. Fungal staining and culture of the lesion obtained by fine needle aspiration (FNA) of the thyroid gland can confirm the diagnosis. Results of thyroid function testing can be normal or may reveal thyrotoxicosis or hypothyroidism.

TREATMENT

Antifungal therapy is the mainstay of treatment. Voriconazole is the first line agent for invasive aspergillus infection. Adding echinocandin (capsofungin or antidulafungin) along with voriconazole may provide marginally better outcomes in patients who are immunocompromised (44,45). Cotrimoxazole is the preferred therapy for pneumocystis infection. The choice of antifungal therapy depends on the type of fungus and the prevalent pattern of antifungal resistance. Surgical debridement may be required especially if there is a possibility of tracheal compression due to mass effect. Symptomatic treatment may be required in the thyrotoxic phase resulting from acute damage to the gland. The thyroid gland fails to recover in a minority of patients. They should be treated with thyroid hormone replacement. Outcome of fungal thyroiditis has improved over the last two decades with advances in antifungal therapy (43).  

Disorders of Calcium Metabolism

Fungal infections can alter calcium and vitamin D metabolism. The common metabolic bone disorders are described in the following section.

MONOCYTE 1α HYDROXYLASE MEDIATED HYPERCALCEMIA

Etiology and Pathogenesis

Conversion to the active 1,25-dihydroxyvitamin D [1,25(OH)₂D] from 25-hydroxyvitamin D [25(OH)D] occurs primarily in the kidney. The renal enzyme 25(OH)D-1α hydroxylase (CYP27B1) responsible for the conversion, is tightly regulated by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), and the serum 1,25(OH)₂D concentration. The activated mononuclear cells and macrophages also exhibit 25(OH)D-1α-hydroxylase activity. The 1,25(OH)₂D synthesized in these cells normally exert a paracrine effect on growth and differentiation of cells. In granulomatous disorders, such as sarcoidosis, tuberculosis, and fungal infections, the 1,25(OH)₂D production in monocytes is dysregulated resulting in hypercalcemia. The monocyte 25(OH)D-1α-hydroxylase is resistant to the regulatory mechanisms and the lack of calcium-mediated negative feedback predisposes to hypercalcemia  (46). PTH-independent hypercalcemia is described in chronic fungal infections, such as histoplasmosis, coccidioidomycosis, para-coccidioidomycosis, candidiasis, cryptococcosis, and pneumocystis.

Clinical Profile

The fungal infections associated with 1α-hydroxylase mediated hypercalcemia can occur in both immunocompromised and immunocompetent hosts. In a review summarizing 16 cases of histoplasmosis induced hypercalcemia, 68.7% (11/16) were immunosuppressed. The common presentations were with polyuria, constipation, altered sensorium, and renal insufficiency (47). Hypercalcemia is also reported in cryptococcus and pneumocystis infections in individuals with HIV/AIDS (48–50). Hypercalcemia can be an early marker of pneumocystis pneumonia in renal transplant recipients (51,52).  

Laboratory Features

Patients present with elevated serum calcium and phosphate levels, suppressed PTH values, normal 25(OH)D, and increased 1,25(OH)₂D concentrations. Serum angiotensin-converting enzyme (ACE) levels can be elevated (47).

Treatment

Hypercalcemia resolves with resolution of the infection after institution of successful antifungal therapy. Hydration, calcitonin, and bisphosphonates can be considered to lower calcium till the effect of antifungal medication occurs (47). Steroids can be used in resistant cases but should be initiated only under appropriate antifungal coverage. Fatalities have been reported when the cases have been misdiagnosed as sarcoidosis and steroids initiated without antifungal drugs (53,54). Some cases show transient worsening of hypercalcemia probably mediated by immune reconstitution inflammatory syndrome (55). Also, initiation of antiretroviral therapy in patients with HIV/AIDS infected with cryptococcus, might cause hypercalcemia. This may be due to restoration of granulomatous host response (56).

PARATHYROID HORMONE REALTED PROTEIN (PTHrP) MEDIATED HYPERCALCEMIA

Coccidioidomycosis infection is associated with hypercalcemia. However, the mechanism of hypercalcemia in coccidioidomycosis is not related to autonomous 1,25(OH)₂D production. It could be due to osseous coccidioidomycosis in some cases, but in the majority of cases it occurs without bony lesions. Serum PTH levels and 1,25(OH₂)D levels were either suppressed or normal (57).  Expression of PTHrP by the granulomatous tissue has been documented in coccidioidomycosis. The serum PTHrP levels are elevated in cases with hypercalcemia and presumed to be the possible mechanism. The PTHrP levels return to normal along with resolution of hypercalcemia after successful antifungal treatment  (58).

OTHER DISORDERS OF CALCIUM METABOLISM

Histoplasmosis-induced hypercalcemia has been postulated to result from excess expression and secretion of osteopontin by histiocytes in granulomas (59). Osteopontin can activate osteoclasts and subsequently lead to bone resorption (60). However, currently there is insufficient evidence to support this hypothesis. 

Hypoparathyroidism has also been described in HIV/AIDS with pneumocystis infiltrating the parathyroid glands. It causes hypocalcemia and hyperphosphatemia (61).

Fungal Infection of the Adrenal Gland

The adrenal gland is the commonest endocrine organ to be affected by infections including mycosis. Adrenal fungal infection can be asymptomatic and get detected as an incidental finding during radiological imaging, or can manifest with symptoms of adrenal insufficiency (62,63).

ETIOLOGY AND PATHOGENESIS

Unlike the other endocrine organs, isolated adrenal involvement can be seen as a manifestation of endemic mycoses in immunocompetent hosts by histoplasmosis, paracoccidioidomycosis, blastomycosis, and other fungal organisms (64–66). The susceptibility to develop primary adrenal infection or disseminated fungal disease is however more often seen in the immunocompromised individuals with HIV/AIDS, or in those receiving immunosuppressive therapy such as solid organ transplant recipients (67). Predisposition of the adrenal glands to fungal infections is postulated to be due to suppression of cell-mediated local immunity caused by high local glucocorticoid levels (68). More often than isolated involvement, the adrenal gland is involved as a part of disseminated infection. Histoplasmosis and paracoccidioidomycosis are the commonest fungal infections reported to have adrenal disease at autopsy (67,69).

Affinity for different adrenal zones might vary for different fungal infections. Paracoccidioides species has affinity for zona reticularis as well as zona glomerulosa leading to decreased dehydroepiandrosterone sulfate and aldosterone levels, respectively (59,70,71). The large fungal cells cause embolic infection of the small vessels of the gland subsequently leading to endovasculitis, granuloma formation and caseous necrosis (67,72). In patients with histoplasmosis, zona fasciculata and reticularis are preferentially affected owing to the presence of high concentration of cortisol (73). Vasculitis of downstream medullary vessels starting from zona fasciculata induce glandular destruction and subsequent caseation necrosis  (68,74).

CLINICAL FEATURES

The spectrum of manifestations of fungal adrenal involvement can vary from asymptomatic cases detected incidentally to frank adrenal crisis. Occasionally, adrenal involvement can get masked by the disseminated fungal disease or the underlying immunocompromised state (67). Many of the patients despite bilateral adrenal infection do not develop adrenal insufficiency, as destruction of more than 90% of adrenal cortex is required for the disease to manifest (59). Some studies have observed lower prevalence of adrenal involvement in immunocompromised hosts, presumably due to the inability to launch a granulomatous response in the gland (75,76).

Addison’s disease is most frequently reported with histoplasmosis and paracoccidioidomycosis, given their high affinity for adrenal glands. In a review of 252 cases of adrenal histoplasmosis, adrenal hypofunction was confirmed in 41.3%. Almost all the cases were secondary to chronic disseminated pulmonary histoplasmosis although isolated adrenal involvement has also been reported (77). A study of 546 cases of paracoccidioidomycosis from Brazil documented adrenal involvement in only 5% (n = 27) (78). Another review revealed partial adrenal insufficiency in 33–40% of cases, and frank symptoms in 3–10% cases (79).  Patients with diminished adrenal reserve often require glucocorticoid supplementation during periods of stress or after initiating antifungal agents known to affect steroidogenesis. There are reports of blastomycosis, pneumocystis, and cryptococcus causing adrenal insufficiency as well (80–82). The clinical features of primary adrenal insufficiency include fatigue, loss of appetite, weight loss, orthostatic hypotension, and hyperpigmentation (66,83).

DIAGNOSIS

Fungal infection of the adrenal glands can be asymptomatic and detected incidentally on abdominal imaging. Radiographically bilateral symmetric adrenal enlargement is seen with histoplasmosis whereas paracoccidioidomycosis and blastomycosis cause asymmetric and occasionally unilateral involvement (81,84–86). Other radiographical features include peripheral enhancement, central hypoattenuation, preserved contour, and calcifications (66,67). These features help to differentiate from other disorders such as metastatic disease where the adrenal contour is distorted and autoimmune adrenalitis, where the glands are atrophic (66,67,87,88).

The laboratory findings such as hyponatremia and hyperkalemia are often seen but the diagnosis of adrenal insufficiency is confirmed with the short Synacthen test (SST) or cosyntropin test (250 ug of Synacthen, im or iv) in chronic and stable cases. In a patient with suspected Addisonian crisis, a blood sample collected for estimation of serum cortisol and adrenocorticotrophic hormone (ACTH) before initiating glucocorticoid replacement can be helpful. A formal evaluation by SST can be performed later. Simultaneous estimation of plasma renin and aldosterone to determine mineralocorticoid reserve can be considered. (66).

The confirmation of fungal etiology might necessitate fungal staining or culture of the biopsied material. In disseminated disease, a more accessible site like skin lesion or affected lymph node can be biopsied instead of the adrenal gland.

MANGEMENT AND PROGNOSIS

Initiation of antifungal therapy at the earliest is essential to salvage adrenal function. Recovery has been reported in a few cases with histoplasmosis and paracoccidioidomycosis (59). However, frequently adrenal insufficiency is irreversible and lifelong glucocorticoid replacement is required. Mineralocorticoid replacement with fludrocortisone may additionally be necessary (83). Onset of  adrenal insufficiency in paracoccidioidomycosis can occur after initiation of antifungal therapy from the fibrosis that occurs during recovery (79,89).

Fungal Infection of the Pancreas

The pancreas is normally resistant to fungal infection. Fungal affection of the pancreas usually occurs in an inflamed gland in the presence of underlying necrosis. Although rare, the prevalence of fungal pancreatitis is on the rise.

ETIOLOGY AND PATHOGENESIS

Candida (C. albicans and C. glabrata) is the most common etiology responsible for fungal pancreatic infections (90). Pneumocystis, aspergillosis, and cryptococcosis have also been reported to affect the pancreas (91–93). The risk factors for fungal infection are necrotizing pancreatitis, use of broad-spectrum antibiotics, abdominal surgery, prolonged total parenteral nutrition, indwelling catheters, and an immunosuppressed state. The mode of spread could be translocation from the gut, hematogenous spread, or external seeding (90).

CLINICAL COURSE AND MANAGEMENT

The clinical features of fungal infection of the pancreas are non-specific. Abdominal pain, fever, and a palpable abdominal mass can occur (94). Most cases of fungal pancreatitis occur on the backdrop of recent necrotizing pancreatitis (90,94). In a study of 92 patients with necrotizing pancreatitis, 22 (24%) had evidence of candida infection in the surgical necrosectomy material (95). Candida was demonstrated in 27% of aspirates from walled-off necrosis occurring after acute pancreatitis (96).  Rare cases of recurrent pancreatitis from candida have also been described (97,98).

Fungal culture and staining of percutaneous aspirates, or necrosed tissue obtained during surgery, are necessary to establish the diagnosis. Antifungal therapy and surgical drainage and debridement are the mainstay of therapy. Mortality rates are higher if candida infection is present (95).

Fungal Infection of the Testis

ETIOLOGY AND PATHOGENESIS

Fungal epididymo-orchitis can occur in isolation or as a part of disseminated infection. The fungi reported to infect testis and epididymis include candida, blastomycosis, histoplasma, aspergillus, and cryptococcus (99–103). Both C. albicans and C. glabatra can cause epididymo-orchitis by retrograde transport from infection in the urinary tract. Risk factors comprise diabetes mellitus, instrumentation of the urinary tract, urinary obstruction, or recent antibiotic usage (104). The majority of blastomycosis infections were associated with systemic diseases (105). Granulomatous epididymo-orchitis can also occur as a part of disseminated histoplasmosis in immunocompromised state (106).  

CLINICAL COURSE AND MANAGEMENT

Most patients present with unilateral or bilateral pain and swelling of the scrotum. Onset can be acute or insidious with duration of symptoms lasting for days to months (104). In contrast, bacterial infection is almost always unilateral with an acute onset of scrotal swelling, redness, and pain. Some fungal infections may remain asymptomatic and get detected on autopsy (102). Fungal epididymo-orchitis is also recognized as a cause of azoospermia and infertility (107). This is mainly due to direct gonadal invasion but can also be due to anti-sperm effects induced by fungi and by secreted mycotoxins (59). C. guilliermondii and C. albicans can affect sperm viability and motility (108). Antifungal agents are the mainstay of treatment. Surgery may be required in some cases.

Fungal Infection of the Ovary

ETIOLOGY AND PATHOGENESIS

Pelvic inflammatory disease (PID) refers to infection of the upper genital tract usually occurring in reproductive age females. A tubo-ovarian abscess (TOA) is a sequela of PID. It is a complex adnexal mass resulting from ascent of the infection through the fallopian tube (109). Though the common causative organisms are bacteria such as Chlamydia trachomatis and Neisseria gonorrhoeae, fungal infections are also recognized as an important etiological agent (110). It can also be a part of disseminated infection (111–113). C. albicans as well as other candida species such as C. glabrata and C. keyfr have been described to cause TOA (114–116). Intrauterine devices, diabetes, and morbid obesity are the typical risk factors (114,117). There are rare reports of female genital coccidioidomycosis (112,113,118).

CLINICAL COURSE AND MANAGEMENT

The usual presentation is that of a pelvic infection not responding to conventional antibiotics (117). Presenting symptoms can be dysmenorrhea, menstrual irregularities, menorrhagia, anovulation, and infertility. Occasional patients present with severe lower abdominal pain, fever and vomiting (116).  

Fusarium toxin zearalenone and its metabolite zearalenol can be present as a contaminant in cereals and usually enter the food chain as pesticide. It is a non-steroidal estrogen mycotoxin with strong affinity for estrogen receptors (119). The resulting hyperestrogenism has the potential to cause infertility by suppressing luteinizing hormone (LH) and progesterone secretion and also can have a carcinogenic effect on the breast (120).

FUNGAL INFECTIONS OCCURING IN ENDOCRINE DISORDERS

Individuals with certain endocrine disorders such as diabetes mellitus and Cushing’s syndrome are predisposed to fungal infections as a result of the associated immune dysfunction. Both pathogenic and opportunistic fungi can cause infection in these conditions. APS1 is an endocrine syndrome characterized by CMC (121). The common fungal infections occurring in individuals with endocrine dysfunction are discussed below. Other fungal infections like coccidioidomycosis and aspergillosis are also known to occur at a higher frequency in individuals with diabetes.

Fungal Infections in Patients with Diabetes

Diabetes is known to affect both innate and adaptive immunity. Hyperglycemia also induces critical alterations in cytokine signaling (122). Fungal infections in general occur at a slightly increased frequency in diabetes, especially if glycemic control is poor. However, certain fungal infections like mucocutaneous candidiasis and invasive mucormycosis have a strong association with diabetes (123).

CANDIDIASIS

Infection with candida is common in individuals with diabetes (124) . Genital candidiasis is often an indicator for undetected or poorly controlled diabetes. Increased hydrolytic enzyme activity and hydrophobicity along with altered biofilm formation have been proposed as possible mechanisms that favor candida infection in diabetes (125,126). The common sites and clinical characteristics of candida infection in diabetes are summarized in table 5.

KOH - potassium hydroxide, SGLT2 - Sodium-glucose cotransporter-2, COPD – chronic obstructive pulmonary disease, PPI – proton-pump inhibitor, PAS – Periodic Acid Schiff, PCR – polymerase chain reaction, TPN – total parenteral nutrition.

MUCORMYCOSIS

Mucormycosis refers to a group of infections caused by fungi of the order Mucorales present ubiquitously in the environment. Individuals with uncontrolled diabetes or those who are immunosuppressed are characteristically affected. The most common presentation is rhino-orbital-cerebral mucormycosis, though pulmonary, gastrointestinal, cutaneous, and renal infection can also occur (145). Several cases of mucormycosis have been reported recently following SARS COV-2 disease (146). Around 40% of the patients had received corticosteroids within the month before the diagnosis of mucormycosis. Diabetes with ketoacidosis (DKA) is 50% more likely to develop mucormycosis than without DKA. The prognosis is poor and mortality rates remain high. The rhino-orbital-cerebral form is characteristically associated with diabetes and detailed below.

Pathogenic Organisms

The pathogenic fungi belonging to order Mucorale customarily associated with human infections are Rhizopus, Mucor,and Lichtheimia (formerly Absidia and Mycocladus). The rarer pathogens include Rhizomucor, Cunninghamella, Apophysomyces, and Saksenaea (147).  Infection occurs presumably from inhalation of spores.

Pathogenesis

Patients with diabetes, defects in phagocytic function (such as neutropenia or glucocorticoid treatment), and/or elevated levels of free iron which supports fungal growth in serum and tissues are prone to mucormycosis. DKA is a risk factor for developing rhino-orbital-cerebral mucormycosis, as acidosis leads to dissociation of iron from sequestering proteins, which aids increased fungal survival and virulence (148). Moreover, the ketoacid -hydroxybutyrate facilitates fungal adherence and penetration into tissues, by increased expression of fungal receptors (149). Apart from ketoacidosis, hyperglycemia itself may contribute to the risk of mucormycosis by four possible mechanisms: (i) disruption of normal iron sequestration due to hyper-glycation of iron-sequestering proteins; (ii) phagocytic dysfunction; (iii) enhanced expression of a mammalian cell receptor (GRP78) that binds to Mucorales, enabling tissue penetration; (iv) enhanced expression of CotH, a Mucorales-specific protein that binds to  GRP78 and mediates host cell invasion (150). The risk factors for mucormycosis are summarized in table 6.

Clinical Features

Rhino-orbital-cerebral mucormycosis is the most common form of the disease whereas lung, gastrointestinal, renal, and cutaneous involvement are less frequent (145). Initial symptoms of rhino-orbital-cerebral mucormycosis include eye or facial pain and facial numbness followed by conjunctival suffusion and blurring of vision. Facial erythema with or without edema may be present. Fever occurs in only half of the cases (151). Black, necrotic eschar develops over the palate or in the nasal mucosa. In untreated cases, infection spreads from the ethmoid sinus to the orbit which involvement of extra-ocular muscles. It results in proptosis, typically with chemosis. Infection might further extend from the orbit to the frontal lobe of the brain via hematogenous route or contiguous dissemination. It may extend to cavernous sinus as well via venous drainage (147). The clinical features are summarized in table 7.

Diagnosis

Clinical features, mycological, and histological investigations and imaging with CT or MRI are necessary for establishing the diagnosis and assessing the extent of spread. If sinusitis is suspected, endoscopy should be performed. Histopathological examination of infected tissue demonstrates characteristic wide, thick walled, ribbon like, aseptate hyphal elements that branch at right angles. Fungal culture of specimens is strongly recommended for genus and species identification, and for antifungal susceptibility testing (145). PCR-based technique and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) can assist to confirm fungal etiology if cultures are negative (145,152). MRI of the cranium including the sinuses and orbit should be done to delineate the extent of involvement (145). CT scan can help to assess the extent of bony erosion and can be considered if MRI is not readily available.

Treatment and Prognosis

Surgical debridement of the necrotic tissue in combination with intravenous lipid preparations of amphotericin B are the mainstay of therapy. It is also important to restore euglycemia and correct acidosis as soon as possible. The recommended dose of lipid formulation amphotericin B is 5mg/kg/day. There is evidence to support a higher dose of 10 mg/kg/day in cases of CNS involvement. There is no consensus on total duration of therapy but it usually takes weeks to months for completely cure these infections. It is critically important to monitor for adverse effects of amphotericin B especially nephrotoxicity and electrolyte imbalance. Posaconazole or isavuconazole can be considered as oral step down therapy, as salvage therapy, or if amphotericin B related adverse effects precludes its further use (145). Repeat surgery may be necessary if the infection progresses. Prognosis is poor especially if there is associated CNS involvement.

DERMATOPHYTES

Dermatophytosis are caused by filamentous fungi belonging to the genera Microsporum, Epidermophyton, and Trichophyton. Dermatophytes cause infection of skin, hairs, and nails and derive nutrition from keratin present in these tissues. Dermatophytosis is known to occur commonly in individuals with diabetes. Infection of the hair is referred to as tinea capitis (scalp) and tinea barbae (beard). Infection of the body surface in general is called tinea corporis while that of groin is known as tinea cruris.

Skin infection with dermatophytes occurring over the feet is called tinea pedis. It can cause micro-fissuring that may predispose to secondary bacterial infection and subsequently to diabetic foot. The other form of dermatophyte infection affecting feet is onychomycosis or tinea unguium (153). Tinea pedis and onychomycosis are commonly causes by the anthropophilic dermatophytes T. rubrum, T. interdigitale and E. floccosum (154). Uremic patients on hemodialysis more often have dystrophic nail changes and are at increased risk of developing onychomycosis (155). Dystrophic nails in onychomycosis look thick, brittle and discolored, often with a yellow shade. It may also lead to separation of the nail plate from the nail bed (onycholysis). Paronychial inflammation of the nail edge surrounding skin is a characteristic feature (156). Early recognition and treatment of tinea pedis and onychomycosis can prevent ominous complications like diabetic foot.

Clinical features along with KOH preparation of scrapings from affected area are usually adequate to establish the diagnosis. Treatment mainly includes topical and oral agents with activity against dermatophytes. The commonly applied topical agents includes azoles, allylamines, butenafine, ciclopirox, and tolnaftate. Oral therapy usually involves use of terbinafine, itraconazole or fluconazole (157).

Fungal Infections in Cushing’s Syndrome

The susceptibility of individuals with Cushing’s syndrome to fungal infection is well recognized. Both endogenous and exogenous hypercortisolism are associated with opportunistic fungal diseases. Hypercortisolism induces immune dysfunction by multiple mechanisms (158).  The major defects induced by excess cortisol are depicted in table 8. Among the subtypes of endogenous Cushing’s syndrome, fungal infections are more commonly seen in the syndrome of ectopic ACTH secretion. Propensity for fungal infections in exogenous Cushing’s syndrome depends on both, the intensity of glucocorticoid therapy and relative virulence of the offending fungus. With respect to glucocorticoids, it depends on administration route, dose, potency, and duration of treatment (159). The commonly reported fungal infections in Cushing’s syndrome are discussed below.

CD - cluster of differentiation, Th – T helper cells, NF – nuclear factor

CANDIDIASIS

In immunocompromised states such as Cushing’s syndrome, candida species may cause superficial infections like cutaneous candidiasis, oropharyngeal candidiasis, esophagitis, or vulvovaginitis. Cases of candida endophthalmitis have also been described (160). It may also disseminate in the bloodstream to cause candidemia. Glucocorticoid may augment biological fitness of candida species, by enhancing its adhesion to epithelial cells. C. albicans is the most common species reported though infection with C. glabrata, C. parapsilosis and C. tropicalis can also occur (159).

ASPERGILLUS

Aspergillus is associated with invasive fungal infection in endogenous Cushing’s syndrome as well as in those receiving exogenous glucocorticoids (161) . Most common species to cause invasive infection are A. fumigatus, followed by A. flavus, A. terreus, and A. niger. The usual portal of entry for aspergillus is typically the pulmonary tract. However, later it might get disseminated systemically and severe cases requiring emergency bilateral adrenalectomy for control of hypercortisolism has been reported (162). Apart from immune dysfunction, glucocorticoids can induce alterations in the biology of aspergillus species to increase its invasiveness. For example A. fumigatus and A. flavusshowed increased growth on in-vitro exposure to pharmacological doses of hydrocortisone (163).

PNEUMOCYSTIS

P.  jirovecii is usually seen in immunocompromised patients. Severe P. jirovecii pneumonia even leading to fatal outcome are described in cases of endogenous Cushing’s syndrome (164). The infection is often unmasked once treatment for hypercortisolism is commenced. The restoration of immune response with lowering of cortisol levels presumably induce the inflammatory changes and result in manifest disease (165,166). A review of 15 cases of P. jirovecii pneumonia, reiterated the same observation of immune reconstitution related worsening of symptoms after treatment initiation. In 13 of these cases symptoms were triggered after cortisol-lowering therapy was started. Interestingly, all but one if these patients had ectopic Cushing’s syndrome. All the cases were characterized by severe hypercortisolemia and the outcome was fatal in 11 cases (167). Patients with Cushing’s syndrome, especially those with severe hypercortisolemia might benefit from prophylaxis with cotrimoxazole before beginning cortisol-lowering therapy.

CRYPTOCOCCOSIS

C. neoformans is another opportunistic infection where Cushing’s syndrome is a predisposing factor. The route of entry is inhalational. It may cause pneumonitis or disseminate systemically to cause more severe infections, such as meningitis and meningoencephalitis (168). Fatal cases have been reported (169,170). The presence of coexisting diabetes might further increase the risk of infection (171).

Glucocorticoid-induced immunosuppression has a few unique characteristics noted with cryptococcosis. For example, alveolar macrophage capacity to attach to and ingest is diminished by cortisone acetate, which potentially may lead to dissemination of the fungus (172). Moreover, chemotactic activity of cerebrospinal fluid toward polymorphonuclear (PMN) leucocytes and monocytes, is substantially reduced by glucocorticoid administration. This leads to lack of PMN leucocyte influx in cerebrospinal fluid and subsequent inability to eradicate fungi like C. neoformans with tropism for the CNS. Glucocorticoid-induced abnormalities of microglial cells further intensify this attenuation. Thus, individuals with hypercortisolemia are predisposed to cryptococcal meningitis (173).

HISTOPLASMOSIS

Pulmonary histoplasmosis has been reported in association with endogenous Cushing’s syndrome (174). Patients receiving glucocorticoids may develop primary or reactivated infections by endemic fungi (175). There are reports of pulmonary histoplasmosis after prolonged glucocorticoid therapy from non-endemic countries as well (176). H. capsulatum, the usual pathogen in most cases of histoplasmosis, enters through the respiratory tract and causes pulmonary histoplasmosis but can also disseminate to cause systemic infection. Pathological features of histoplasmosis are atypical in patients treated with glucocorticoids. Discrete granuloma formation is prevented by the anti-inflammatory properties of glucocorticoids (175).

OTHER FUNGAL INFECTIONS

Other fungal infections reported with hypercortisolemia are C. immitis, mucor, fusarium and blastomyces (159). Besides the heightened risk of fungal inspection in hypercortisolemia, the other concerning issue is masking of the signs and symptoms of infections due to the anti-inflammatory properties of glucocorticoids. Recognition of infections may be delayed in presence of hypercortisolemia, and a high index of suspicion is required for early diagnosis. Treatment of fungal infection must include prompt correction of hypercortisolism and aggressive antifungal therapy.

Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1

Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by the classical triad of chronic mucocutaneous candidiasis (CMC), autoimmune hypoparathyroidism, and Addison’s disease. Two of the three classic features should be present to establish the diagnosis of APS1. However, there is a risk of the development of autoimmune diseases affecting almost every organ. APS1 is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) with ectodermal dysplasia occurring in a third of the patients. Ectodermal dystrophy is not related to candidiasis (121). CMC commonly occurs sporadically secondary to AIDS, diabetes, and immunosuppressive treatment (177). C. albicans is the predominant pathogen but infection with other candida species is also described.

PATHOGENESIS

APS1 is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, located on the short arm of chromosome 21. The functioning of following pathways can be altered in APS1, though the specific contribution in increasing susceptibility to candida infection is not well defined.

1. Defects in AIRE gene are associated with autoantibodies to interleukin (IL) 17A, IL17F and IL22, which are key cytokines for the function of the T-helper (Th) 17 cell subset. Loss of function of these cytokines increase susceptibility to candida infections (177).
2. Autoimmunity to mediators involved in antigen presentation by B cells may be an additional factor responsible for susceptibility. This is further corroborated by the response to rituximab (anti-CD 20 antibody that prevents B cell function) to certain components of the disease in individuals with AIRE deficiency (178).

• A defect in Dectin-1, a β-glucan receptor, has been shown to diminish tumor necrosis factor α production in APS-1. Innate immune response is affected as a result (179).

CLINICAL SPECTRUM

CMC is the most common component of APS-1. It has been reported in 80-100% of cases in different series (121,177). Onset of CMC is usually in the first decade and cases can be seen in the very first year of life. Mouth, nails and, less frequently, skin, vagina and the esophagus are affected. The infection tends to be persistent or recurrent. Severity of the infection in variable, however disseminated disease is rare (177).

The oral mucosa is the usual site of infection. All spectra of infection starting from localized ulceration, and redness in mild cases to involvement of entire mouth is described. White or grey membrane covering the tongue or mucosa are visible in the hyperplastic form. Cracks (angular cheilitis or perlèche) occurring at the angle of the mouth is common. The atrophic form has areas of leukoplakia, which is a significant risk factor for carcinoma of the oral mucosa. The finger nails are the other site which is commonly affected. There can be an associated paronychia. Onychomycosis in CMC is particularly resistant to treatment (121,180).

TREATMENT

Oral fluconazole is the preferred therapy. Some patients require suppressive treatment with fluconazole 100 mg three times a week. Emergence of resistance remains a possibility with suppressive therapy. Alternatives for fluconazole refractory disease includes itraconazole, Posaconazole, or voriconazole. Rare cases of systemic disease not responding to azoles might require a lipid formulation of amphotericin B or echinocandins (144).

ADVERSE ENDOCRINE EFFECTS OF ANTIFUNGAL AGENTS

The antifungal drugs such as polyenes, azoles and echinocandins can impact the function of endocrine glands. Azoles are recognized for their adverse effect on adrenal cortex and the gonads. The other drugs are also known to cause endocrine dysfunction though less frequently. These important adverse endocrine consequences of the different antifungal agents are discussed below.

Azoles

The azoles are the one of the most frequently administered systemic antifungal agents. They can be divided into two groups on the basis of their structure. Ketoconazole, which belongs to the imidazole group, is associated with multiple endocrine adverse effect, but seldom used orally as an antifungal agent currently. The newer azoles belonging to the triazole group include fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. Endocrine dysfunction also occurs with the triazoles but is less frequent (181).

ADRENAL GLAND

The azoles exert their antifungal effect by inhibiting the cytochrome P450 (CYP450) enzyme lanosterol 14-α-demethylase (CYP51) mediated conversion of lanosterol to ergosterol, a critical constituent of fungal cell wall.  Mammals do not have this enzyme, but azoles can block the synthesis of glucocorticoids, mineralocorticoids, and sex steroids by blocking CYP450 dependent enzymes involved in steroidogenesis (182).

Ketoconazole

Ketoconazole is a dose-dependent reversible inhibitor of cholesterol desmolase, 17,20-lyase, 11β-hydroxylase, 17α-hydroxylase, and 18-hydroxylase (183). Ketoconazole at doses of more than 200 mg daily can impair glucocorticoid synthesis. Overt adrenal insufficiency is relatively infrequent however it can be seen with doses of 600 to 1200 mg/day, which are often used in the medical management of Cushing’s syndrome (59,184,185). Apart from inhibiting enzymes involved in steroidogenesis, ketoconazole is also a dose-dependent, reversible, competitive antagonist at the glucocorticoid receptor level (186). The inhibitory effect of ketoconazole on adrenal steroid synthesis has been utilized for  the medical management of Cushing’s  syndrome (187).

Fluconazole and Posaconazole

Adrenal insufficiency has been reported with the imidazole derivatives itraconazole, fluconazole, voriconazole, and posaconazole (188–192). Primary adrenal insufficiency induced by fluconazole has been observed in critically ill patient as a result of CYP450 inhibition (193). Fluconazole has been employed for the medical management of Cushing’s syndrome (194). Posaconazole-induced primary adrenal insufficiency resulting from a similar mechanism has been described (190,192).

Itraconazole and Voriconazole

Itraconazole and voriconazole (also ketoconazole) are potent inhibitors of CYP3A4, the enzyme that partially metabolizes glucocorticoids. The resultant decrease in glucocorticoid clearance produces supraphysiological levels of glucocorticoid from inhaled, nasal or oral steroids (195). The clinical profile resembles that of an iatrogenic Cushing’s syndrome later progressing to secondary or central adrenal insufficiency consequent to suppression of the hypothalamic-pituitary-adrenal (HPA) axis (196). Secondary adrenal insufficiency following combined use of glucocorticoids and itraconazole or voriconazole have been described (188,191). Steroids that are predominantly metabolized by the CYP3A4 pathway include methylprednisolone, fluticasone, budesonide and triamcinolone. It may be prudent to consider alternative glucocorticoids such as prednisolone, beclomethasone, or flunisolide that are not predominantly metabolized by CYP3A4 enzymes when voriconazole or itraconazole is being administered (190,191).

Pseudohyperaldosteronism

Posaconazole and itraconazole has been associated with a syndrome of mineralocorticoid excess manifested by low-renin low-aldosterone hypertension and hypokalemia (197). Two distinct mechanisms are implicated in the pathogenesis with significant interindividual differences. Posaconazole can inhibit the enzyme 11 β-hydroxylase (CYP11B1) and prevent the conversion of 11-deoxycortisol to cortisol. Diminished cortisol synthesis triggers adrenal steroidogenesis as a result of loss of feedback inhibition of the HPA axis and causes accumulation of 11-deoxycortisol (and 11-deoxycorticosterone). Even though aldosterone production is reduced due to posaconazole-induced aldosterone synthase (CYP11B2) inhibition, very high levels of 11-deoxycortisol and 11-deoxycorticosterone can overcome that and produce a state of mineralocorticoid excess (197,198). The other mechanism incriminated is blockage of the peripheral cortisol metabolizing enzyme 11 β-hydroxysteroid dehydrogenase 2 (11β-HSD2) leading to an increased ratio of active to inactive cortisol metabolite. Elevated ratios of cortisol to corticosterone and their tetrahydro-metabolites are observed in such individuals (198). There are few case reports of itraconazole and several reports of posaconazole-induced pseudohyperladosteronism (199–202). Therapeutic options include lowering the dose of azoles or changing to alternatives like isavuconazole (198).

GONADS

Male Sexual Dysfunction

Inhibition of 17,20-lyase by ketoconazole impairs production of testosterone in the male gonads (203). The effect can be seen even at a single dose of 200mg, however lower testosterone levels and longer duration of suppression can be seen with an increasing dose (204). Oligospermia and azoospermia as well as decreased libido and impotence have been reported at doses more than 800mg/day (181). Reversible gynecomastia is another manifestation seen due to increase in the estradiol:testosterone ratio partially attributed to displacement of estrogen from sex-hormone binding globulin by the drug (205).

Ketoconazole also binds to androgen receptors thereby blocking androgen signaling (206). Antiandrogenic properties of ketoconazole have been used in the treatment of prostate cancer, autonomous Leydig cell hyperactivity in children with precocious puberty, and topical therapy for androgenetic alopecia (207–209).

Fluconazole in contrast to ketoconazole does not affect testosterone synthesis (210). A single case of posaconazole induced gynecomastia has been reported. Inhibition of the CYP11B1 enzyme by the drug stimulates compensatory adrenal steroidogenesis. Increased peripheral conversion of adrenal androgens to estrogen was presumed to induce gynecomastia after posaconazole use. The other possible hypothesis could be reduced catabolism of estrogen in the liver due to blocking of CYP3A4 and CYP3A7 (211).

Female Reproductive Dysfunction

Ketoconazole reduces estrogen levels in females. Reduction of estrogen levels could be due to aromatase inhibition or androgen synthesis blockade. Estrogen precursor deprivation from decreased androgen synthesis is likely to be the predominant mechanism (59). In animal studies, ovarian progesterone production is impaired thereby preventing uterine implantation (212). Ketoconazole has been used in treatment of polycystic ovarian syndrome and ovarian hyperthecosis, given its ability to substantially block ovarian androgen synthesis (213). Itraconazole when co-prescribed with simvastatin, induced metrorrhagia in a 69-year old lady, presumably occurring as result of low-estrogen breakthrough bleeding (214). Itraconazole can also enhance estrogen metabolism interfering with efficacy of oral contraceptives (215). Fluconazole on the other hand can increase estrogen levels by inhibiting its metabolism and is not associated with risk of contraceptive failure (216).

HYPONATREMIA

Voriconazole use has been associated with severe hyponatremia. The median time to onset of hyponatremia is 6-26 days (217). Severe hyponatremia, volume depletion, elevated antidiuretic hormone (ADH), and plasma renin activity along with high urinary sodium suggestive of salt-losing nephropathy were observed after voriconazole administration (218). Syndrome of inappropriate ADH secretion (SIADH) has been implicated as another possible mechanism and euvolemia is the critical distinguishing feature from salt-losing nephropathy (219). The toxic effect of voriconazole is concentration-dependent and therapeutic drug monitoring has been found to be useful for prevention and dose adjustment for hyponatremia (220). The risk of hyponatremia increased with trough concentrations > 7 mg/L and the dose should be modified to maintain levels below that threshold (181). An interesting observation was predisposition to develop voriconazole induced hyponatremia among Asians, in whom polymorphism of CYP2C19 is more common (221). CYP2C19 is the enzyme that metabolizes voriconazole and dosing depending on genotype has been proposed as a means to avert its adverse effects including hyponatremia (222,223).

FLUORIDE-INDUCED PERIOSTITIS

There are several reports of voriconazole-induced periostitis presumably related to excess fluoride released from the three fluorine atoms present in the molecule (224–228). A 400 mg tablet of voriconazole contains approximately 65 mg of fluoride, however only 5% of the fluoride is generated from the drug in free form (181,224). The other fluorinated azoles fluconazole and posaconazole contain two atoms of fluorides and have not been associated with fluorosis and periostitis (225).

A review summarizing 98 cases of periostitis, reported the median age to be 59 years with onset of symptoms between 6 weeks to 8 years after drug exposure. Presenting features are muscle and bone pain. Affection of almost any skeletal site has been described (229). Ribs and ulna are the most common site of involvement. The other involved sites include tibia, clavicle, femur, radius, fibula, scapula, and humerus (224,229).

The serum fluoride and alkaline phosphatase levels are significantly higher in those with periostitis compared to those without (224). The plain radiograph reveals multiple areas of periosteal thickening along with formation of new bones which may take the form of an exostoses or can be fluffy. The radiological findings are analogous to periostitis deformans observed in fluoride intoxication (230).  Bone scan shows increased tracer uptake but unlike hypertrophic osteoarthropathy tend to be asymmetric (224). Discontinuation of voriconazole usually results in improvement in the majority of cases. Substitution by a non-fluorinated azole such as itraconazole can be considered when continued antifungal coverage is necessary. Replacement by posaconazole has also been beneficial (228). 

OTHER ENDOCRINE ABNORMALITIES

High dose ketoconazole (1200mg/day) may rarely cause hypothyroidism by interference with iodine and thyroid peroxidase (231). Ketoconazole is also an inhibitor of 25(OH)D-1α hydroxylase (CYP27B1) leading to decreased 1,25(OH)₂D levels (232). Hypercalcemia induced by sarcoidosis, tuberculosis and other granulomatous disorders respond to treatment with ketoconazole (233,234). Both ketoconazole and fluconazole are treatment options for idiopathic infantile hypercalciuria that occurs from CYP24A1 (24-hydroxylase) gene mutations (235,236). The effects of ketoconazole on enzymes regulating vitamin D has also been explored for treatment of prostate cancer (208,237).   

There are rare reports of pancreatitis with fluconazole, itraconazole, and voriconazole (181). Voriconazole, ketoconazole, and fluconazole have been implicated as a cause of hypoglycemia (238,239). The hypoglycemia could be due to hyperinsulinemia resulting from decreased degradation of insulin (240). The metabolism of sulfonylureas can be inhibited by fluconazole thereby increasing the risk of hypoglycemia in individuals receiving both these drugs (241,242).

Polyenes

The polyenes currently in medical use are nystatin and amphotericin B. Use of nystatin is limited to topical application. Amphotericin B deoxycholate is associated with higher risk of toxicity as compared to its lipid preparation. The lipid formulations of amphotericin B are expensive but the risk of adverse effect is less. Electrolyte abnormalities resulting from tubular damage is the predominant endocrine dysfunction described with amphotericin B. Rare cases of pancreatitis have occurred with liposomal amphotericin B (243).  

TUBULAR DAMAGE

Clinical manifestations of amphotericin B induced nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic acidosis resulting from distal renal tubular acidosis, and polyuria due to nephrogenic diabetes insipidus (DI) (244–246). The mechanism for DI involves a decrease in aquaporin 2 expression in the kidney medulla, that makes the collecting tubules insensitive to ADH (244). Although the risk of nephrogenic DI with lipid preparations of  amphotericin B is significantly less, cases have still been described (247). Nephrogenic DI can be managed by amiloride plus hydrochlorothiazide, or indomethacin (248).

Nephrogenic DI can also be induced by hypokalemia caused by amphotericin B (249). Hypokalemia is more common with amphotericin B deoxycholate but is also recognized  with lipid preparations of amphotericin B (250). Amphotericin B can induce apoptosis of renal tubular cells and also enhance tubular permeability by damage to lining epithelium (251). Renal magnesium loss can also result from amphotericin B. PTH secretion is  affected by hypomagnesemia and that may subsequently lead to hypocalcemia (252). Monitoring and supplementing potassium and magnesium is an important adjunct to prevent adverse consequences of amphotericin B therapy (253).

Echinocandins

Capsofungin, micofungin and antidulafungin are the three echinocandins currently in clinical use.  These agents, unlike azoles or amphotericin B, do not usually cause adverse endocrine effects. Micafungin is rarely reported to cause pancreatitis (254). Caspofungin has been reported to induce hypercalcemia in an infant by an undefined mechanism (255).

Other Agents

Oral potassium iodide is used in treatment of cutaneous sporotrichosis (256). It may precipitate thyrotoxicosis in patients with incipient Graves’ disease or multinodular goiter in areas of relative iodine deficiency (Jod-Basedow disease).  Hypothyroidism can occur in those with excessive autoregulation on prolonged exposure (Wolff-Chaikoff effect) (257).

CONCLUSION

Although fungi are ubiquitous within the environment, very few are considered true pathogens and affect healthy individuals only in limited circumstances. The majority of fungi are opportunistic and immune dysfunction in endocrine disorders increase susceptibility to fungal infection. On the other hand, fungal diseases especially in immunocompromised host can disseminate and affect various endocrine glands thereby impairing their function. Antifungal therapies too contribute to endocrine adverse effects. Moreover, in few endocrinological conditions like Cushing’s syndrome, signs and symptoms of fungal infection can be masked due to effect of hypercortisolemia. A high index of suspicion is mandated in such cases, as delayed or missed diagnosis could dramatically influence the outcome. An understanding of the complex relationship between fungal infection and endocrine disorders is necessary in modern-day medicine as both these conditions are increasingly prevalent.

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ABSTRACT

The adrenal gland in conjunction with the pituitary gland is one of the major components of the endocrine system and regulates blood volume, blood pressure, serum electrolytes, and stress responses. Dysfunction of the adrenal glands may be related to diseases of the adrenal glands or pituitary gland. Adrenal disorders may present either due to structural or functional abnormalities. In the tropical countries, adrenal insufficiency is primarily due to adrenal infection by tuberculosis, adrenal mycosis infections, and adrenal hemorrhages. HIV (Human immunodeficiency virus) related adrenal problems are also common. Adrenal dysfunction due to pituitary disorders still occur frequently in tropical region and include Sheehan’s syndrome, vasculotoxic snake bite, and thalassemia. Adrenal hormone excess typically occurs secondary to exogenous glucocorticoid use. Adrenal disorders that occur in the developed world occur with similar frequencies in tropical regions.

INTRODUCTION  

PRIMARY ADRENAL INSUFFICIENCY  

The causes of primary adrenal insufficiency that are more frequent in tropical regions include infection of the adrenal glands by tuberculosis or mycotic infections. In addition, autoimmune Addison’s disease or adrenal failure as a component of polyglandular syndromes are equally prevalent in tropical regions as is in other parts of the world. 

Adrenal Gland Tuberculosis

Adrenal gland tuberculosis or Tuberculous adrenalitis is the result of infection of adrenal gland by mycobacterium tuberculosis. The infection causes a destructive lesion of the adrenal cortex with uncertain chances of recovery and remains one of the most important causes of Addison’s disease in the tropical countries (1). In fact, the adrenal glands are the most common endocrine organs to be involved in tuberculosis (2). Adrenal gland tuberculosis occurs almost always secondarily due to the hematogenous spread of the bacilli to the gland with the primary focus in lung. Adrenal failure or Addison’s disease clinically manifest when at least 90% of the gland has been destroyed (1,2,3). Though classically the adrenal cortex is involved, the medulla also may be involved in many cases of adrenal tuberculosis (3,4).

PATHOPHYSIOLOGY 

It is interesting to know why the adrenal glands are susceptible to infections. In fact, adrenal gland infections are common in response to a distant infection elsewhere in the body and in disseminated infection. Autopsy examination revealed that the prevalence of adrenal tuberculosis is about 6% in patients with active tuberculosis (4). However, subclinical adrenal dysfunction may be present in about 60-70% of patients with active tuberculosis (5). In any of these situations, there is an exaggerated response of the hypothalamo-pituitary-adrenal axis to produce excess cortisol in response to the stress of infection. This stress induced hypercortisolemia shifts the balance in the Th1/Th2 cell ratio towards a Th2 response (6). This T cell dysfunction (which is primarily responsible for cell mediated immunity) and low DHEA levels increases the host susceptibility to infection to mycobacterium tuberculosis and other organisms (6). Low DHEAS levels have been documented in tuberculosis (1,6). In addition, endotoxin released in response to the hyperactive HPA axis can cause pathological changes in the adrenal glands to increase the susceptibility to infection (7). The intrinsically rich vascularity of the adrenal glands promotes all of these pathophysiological events.

Histopathologically, four classic patterns have been described in adrenal tuberculosis (3). These are:  granuloma (caseating or non-caseating), enlargement of the gland with destruction by inflammatory granuloma, mass lesions due to cold abscesses, and adrenal atrophy due to fibrosis related to chronic infection. Caseating granuloma is the commonest one and this is identified in about 70% of cases (4). However, granuloma with typical presence of Langhan’s giant cell are less common and identified in less than 50% of cases (4), probably due to anti-inflammatory effects of local glucocorticoids. Calcification of the gland is a common but it is present in other chronic infections of the adrenal glands (3). In about 25 % cases the infection may be unilateral (1).

PRESENTATION

Typical symptoms of adrenal gland tuberculosis in a patient with diagnosed tuberculosis (whether or not on anti-tubercular chemotherapy) are mucocutaneous pigmentation in association with chronic ill health, vomiting, postural hypotension, and anorexia (3). The features are similar to Addison’s disease due to other conditions. As the features of progressively evolving adrenal hypofunction are mostly nonspecific, a high index of suspicion is necessary in subjects with diagnosed active tuberculosis especially when pigmentation is absent. However clinical manifestations may take months to years to become apparent.

The patient may also present rarely with frank adrenal crisis with hypotension, hyponatremia, hyperkalemia, and low serum cortisol levels. The crisis may even be precipitated after administration of rifampicin which increases the hepatic metabolism of cortisol in the background of subclinical adrenal dysfunction (8). 

Adrenal tuberculosis may also present as an adrenal incidentaloma. Nonspecific abdominal pain, weight loss, dizziness, and vomiting may lead to imaging of the abdomen which may reveal an incidental adrenal mass often with calcification. The differential diagnosis of Addison’s disease with adrenal enlargement includes (apart from tuberculosis) malignancy, fungal infections, hemorrhage, amyloidosis, sarcoidosis, etc. (3).

Subclinical adrenal dysfunction is also very common and should be actively sought in all cases of active tuberculosis (5).

INVESTIGATIONS

Laboratory Studies

Common laboratory findings include anemia, hyponatremia, and hyperkalemia. In the presence of a positive Mantoux test in association with typical clinical manifestations of adrenal hypofunction, adrenal tuberculosis must be ruled out. Adrenal insufficiency should be ruled out by using a standard protocol. Serum cortisol levels <5 µg/dL and a plasma ACTH more than 2-fold the upper limit of the reference range is suggestive of primary adrenal insufficiency (9). The serum cortisol may remain in the low-normal to mid-normal range in many cases.  However, a standard dose (250 µg) intravenous cosyntropin (Synacthen) stimulation test establishes the diagnosis of adrenal insufficiency when the peak level of cortisol remains below 18 µg/d (9). Random cortisol levels, though useful during an acute crisis, is not usually sufficient to rule out adrenal insufficiency (9). Documentation of subclinical adrenal dysfunction may reveal mineralocorticoid deficiency alone (as demonstrated by raised plasma rennin activity) when stimulated cortisol is within the normal range (8).

Imaging of Adrenal Glands

CT scan of the abdomen is the most important non-invasive investigation with a very good spatial resolution to diagnose adrenal tuberculosis. The findings are usually bilateral and vary with the duration of the disease before diagnosis (1, 3). The most common early findings during the initial 2 years include a mass lesion with smooth adrenal contour preserved. The glands may show central or patchy hypodensity corresponding to areas of caseous necrosis (3). On contrast administration there is peripheral rim enhancement. Calcification is not a common feature in early tuberculosis (3).

With chronic infection, the adrenal glands become small and shrunken, often with associated calcifications and the margins become irregular (3). Though prevalence and intensity of calcification increases with the duration of tuberculosis, this is not a specific finding and may be associated with other conditions.

Though MRI is also done in many cases, this imaging modality has limitations to assess calcification. However, T1 weighted image shows hypointense or isointense areas and T2 weighted image shows hyperintense areas because of necrosis (3).

Percutaneous FNA/ TB PCR 

 For confirmation of adrenal tuberculosis tissue diagnosis is required. CT scan guided fine needle aspiration from the adrenal gland is necessary to obtain adequate tissue specimens (3, 10). Pathological and microbiological confirmation is necessary, especially where there is isolated adrenal involvement. However, it should be remembered that PCR and culture of these specimens for tuberculosis bacilli are not consistently positive (3). Hence a combination of histopathology, PCR, and culture may be necessary to confirm the diagnosis (3). However, routine search for pulmonary tuberculosis with necessary investigations is mandatory.

TREATMENT

Treatment of adrenal insufficiency in tuberculosis requires administration of both glucocorticoids and mineralocorticoids. As the medulla is frequently involved, patients may require higher doses for maintenance of blood pressure. At the same time, rifampicin used in the anti-tubercular regimen is a potent hepatic enzyme inducer and accelerates cortisol metabolism. This also may necessitate a higher dose of glucocorticoids for adequate treatment. However, aldosterone is less likely to be involved. Adrenal crisis is also reported to occur following the administration of rifampicin (11).

Therapy is monitored with blood pressure, body weight, well-being, serum electrolytes and blood glucose. Patients should be also be monitored for over treatment with glucocorticoids with weight gain, blood pressure, decreasing bone mineral density, and other manifestations of Cushing’s syndrome. All subjects should carry a ‘steroid card’ and should be advised strictly on how to increase the dose of glucocorticoid in stressful situations such as fever, infection, vomiting, trauma, etc.

PROGNOSIS FOR ADRENAL FUNCTION RECOVERY

Chances of adrenal recovery with anti-tuberculosis therapy are uncertain and unpredictable. When the disease is diagnosed late, the glandular destruction is usually significant and the gland becomes atrophic, and anti-tuberculosis therapy does not lead to a recovery of adrenal function (12, 13). If therapy is started early before the gland is destroyed recovery may occur (14, 15). It is also suggested that if the gland size remains the same on subsequent follow up CT scans, it is prudent to follow up the patient for adrenal function recovery.

Adrenal Mycosis

HISTOPLASMOSIS 

Adrenal Histoplasmosis caused by the dimorphic fungus Histoplasma capsulatum, is a recognized cause of adrenal insufficiency. Though this opportunistic pathogen is known to affect immunocompromised individuals predominantly (16), it can rarely infect immunocompetent individuals (16, 17).  This is the most fungal infection of the adrenal glands (16, 18).

Involvement of the adrenals can occur during disseminated infection or many years after disease resolution (18). Adrenal involvement can vary from an asymptomatic milder form to a very severe form that presents with extensive bilateral granulomatous involvement of the entire adrenal gland with calcified lesions culminating in acute adrenal insufficiency (18, 19). Rarely the involvement can be unilateral (17). The common differential diagnosis includes tuberculosis, other fungal infections, adrenal metastasis, primary adrenal malignancy, and primary adrenal lymphoma (16). In immunocompetent individuals it commonly presents with a unilateral or bilateral adrenal mass with constitutional symptoms.

The hypothesis for why histoplasmosis involves the adrenal glands with increased frequency includes the local high levels of glucocorticoids in association with a relative paucity of reticulo-endothelial cells within the adrenal gland (6). The gland is destroyed by direct infection that leads to local ischemia and infarction due to perivasculitis, and caseation (6).

Diagnosis depends on imaging studies with pathological confirmation. CT scan of the adrenal glands typically reveals symmetric enlargement with central hypodensity and characteristic peripheral rim like enhancement (20). Frequently calcification is also present, particularly during the healing phase (20). Percutaneous ultrasound or CT guided fine-needle aspiration or biopsy is necessary for tissue diagnosis (18). The characteristic cytopathological findings are the presence of numerous small oval yeast like structures inside the cytoplasm of macrophages (16). On a necrotic background, this yeast like structures inside the macrophages is surrounded by a clear ring of space resembling a capsule. However, the gold standard for diagnosis is documentation of the organism in the culture of pathological specimen (16). Bhansali et al reported a high uptake in adrenal glands in FDG-PET scan in patients with adrenal histoplasmosis (17). 

Treatment for adrenal histoplasmosis depends on the severity of the infection and the condition of the patient. For severe infection in critically ill patient’s amphotericin B is used initially followed by long-term therapy with oral itraconazole (16). Parenteral liposomal amphotericin B is given 3mg/kg body weight for 2 weeks (17). The duration of therapy with itraconazole varies from six months to two years depending on the patient’s condition. For mild to-moderate histoplasmosis, the recommended treatment is itraconazole. The recommended dose is 200 mg twice daily given for 12 months (16). When itraconazole is used, liver enzymes should be monitored on a regular basis (18).  Treatment for adrenal insufficiency follows the same principles as described earlier.

Though the remission rate from adrenal histoplasmosis is high with long-term oral itraconazole, adrenal insufficiency rarely resolves and reversal of adrenal dysfunction can be seen only in some patients after prolonged antifungal therapy (21).  However, histoplasma in adrenals is reported to persist even 7 years after antifungal therapy (22). 

OTHER FUNGAL INFECTIONS

Paracoccidioidomycosis Brasiliensis

Paracoccidioidomycosis brasiliensis is a dimorphic fungus and can cause chronic, progressive, suppurative and granulomatous disease which can lead to adrenal insufficiency (3). The disease is endemic in Latin America. Humans are the accidental host for the organism and females are rarely affected (23). Smoking and alcohol increase the risk. The lungs are the usual portals of entry. Juvenile forms of the disease are also known (23). Apart from frank adrenal crisis, it can present as progressive constitutional symptoms, hyperpigmentation, and low blood pressure with postural drop and bilateral adrenal enlargement in imaging studies with frank adrenal calcification detected by CT scans (24, 25). Histopathology with GMS stain shows multiple budding yeast with steering wheels appearance which is consistent with Paracoccidioides brasiliensis (24). However, confirmation of the organism by culture material is the gold standard for diagnosis. Serology for antibody detection is also useful in the diagnosis. Diagnosis and treatment of adrenal insufficiency is not different than described above for histoplasmosis. P. brasiliensis primarily causes adrenal destruction by embolic infection of small vessels by large fungal cells and granuloma formation (3). Subjects who receive early antifungals with itraconazole over a 1–2-year period may have a full recovery of adrenal function by preventing fungal embolism in adrenal gland vasculature and reducing ischemic necrotic destruction of the gland (3). Hence an early diagnosis is crucial for preventing the progression of adrenal dysfunction. However, persistence of high antibody titer against paracoccidioidomycosis at the end of treatment or during follow-up is a frequent finding in subjects with paracoccidioidomycosis.

Blastomyces Dermatitidis

Blastomyces dermatitidis is also a dimorphic fungus, which has a strong affinity for the adrenal gland for reasons described earlier. Overt adrenal insufficiency is less common and adrenal Blastomyces dermatitidis typically presents as bilateral adrenal incidentaloma during radiological investigations for other reasons (3). The portal of entry is through the lungs and when there is lymphohematogenous dissemination the disease spreads to other organs (26). In situations when it presents as adrenal insufficiency, the presentation, investigations, and management are similar to those described above. Diagnosis is by fine-needle aspiration guided by ultrasound or CT scan followed by cytologic and histologic examinations. However, the gold standard is fungal culture showing thick-walled, broad-based budding yeast cells (27). Treatment is with long term oral itraconazole. In patients with severe manifestations initial treatment with liposomal amphotericin B for 2 weeks could be used.

Cryptocoocus Neoformans

Cryptocoocus neoformans is an encapsulated yeast-like fungus which infects primarily immunodeficient hosts, particularly subjects infected with HIV or lymphohematogenous malignancies (28). In immunocompromised hosts it usually affects the central nervous system and lungs.  However immune-competent individuals may also suffer adrenal cryptococcosis (29). Adrenal dysfunction is uncommon until almost the whole of adrenal gland is infiltrated with C. neoformans and caseating granulomas. Cryptococcosis is diagnosed by fine-needle aspiration biopsy of the adrenal mass. The serum cryptococcal antigen titer is highly elevated. Treatment is with antifungal therapy with fluconazole and amphotericin B. Adrenal enlargement by Cryptococcus may be completely reversible without any abnormality after antifungal treatment (30). Cases not responsive to anti-fungal therapy have been reported to improve after unilateral or bilateral adrenalectomy (28, 29).

Miscellaneous

Pneumocystis jirovecii (previously known P. carinii) occurs in individuals with advanced HIV due to defects in cell mediated immunity. Spread to other organs including the adrenal glands is also possible (3). Adrenal failure associated with coccidioidomycosis and rarely candidiasis has also been reported.

Adrenal Hemorrhage; the Waterhouse Friderichsen Syndrome

This is a condition in which patient presents with acute hypotension and shock due to adrenal insufficiency arising from acute adrenal hemorrhage. The syndrome is typically related to infection with Neisseria meningitides infection (3). However, this is also known to occur in septicemia due to infections with Staphylococcus aureus, Streptococcus spp, Haemophilus influenzae, Corynebacterium diphtheria, etc. (3). Hence this is more common in the tropical region.  The condition is hypothesized to be due to interplay between endotoxemia and elevated ACTH. The adrenal gland is anatomically prone to hemorrhage as it has three separate arterial supplies and does not have proportional venous drainage (3). In endotoxemia, elevated ACTH increases the blood supply several fold in this compromised anatomical setting. At the same time increased adrenaline secretion in relation to stress leads to constriction of adrenal veins, which further increases this imbalance between arterial supply and venous drainage. Management includes immediate fluid replacement and parenteral glucocorticoids apart from the management of the underlying infection.

SECONDARY ADRENAL INSUFFICIENCY 

Adrenal insufficiency secondary to disorders of pituitary gland is also very common in developing countries in tropical regions.  Secondary adrenal insufficiency caused by pituitary tumors and apoplexy, pituitary surgery, radiation therapy, hypophysitis, various genetic disorders, and withdrawal of exogenous steroids are equally common in tropical regions but certain other disorders like Sheehan’s syndrome, thalassemia, and vasculotoxic snake bite induced pituitary failure are more common in tropical regions.

Sheehan’s Syndrome 

Sheehan’s syndrome consists of various degrees of pituitary insufficiency, which develops as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage. The important pathogenetic/predisposing factors include a small sella, increased pituitary volume, vasospasm induced by postpartum hemorrhage, thrombosis, and probable pituitary autoimmunity (31). In developed countries there has been a drastic reduction in the incidence of Sheehan’s syndrome. This is primarily due to the remarkable improvement in obstetric care and availability of rapid blood transfusion. However, this remains as a major cause of hypopituitarism in the other parts of the world.

CLINICAL FEATURES

Most commonly the disorder presents as a lactation failure in the post-partum state and non-resumption of menses following child birth, which was complicated by massive post-partum hemorrhage leading to hypotension and shock. However, it may very rarely occur without massive bleeding or after normal delivery. Patients may present in the emergency with altered sensorium, loss of consciousness, seizure, shock, intractable vomiting, or more commonly with chronic complaints like asthenia and weakness, dizziness, anorexia, weight loss, nausea, and vomiting with a typical history of failure to resume menses and lactation failure following child birth (31). Apart from anterior pituitary hormone deficiency, symptoms like anemia, pancytopenia, osteoporosis, cognitive impairment, and poor quality of life are also present in these patients (31,32).  Very rarely diabetes insipidus may occur. However, the mean age of the participants may be as late as 40 years or more and the mean interval between inciting event to diagnosis may be as high as 10 years or more (33).

Adrenal insufficiency due to ACTH deficiency is reported to occur in up to 100% of cases (in fact deficiency of all anterior pituitary hormones occur in a variable percentage of patients and may be up to 100%) (32). Weakness, fatigue, and postural drop are common manifestations. Hyponatremia is particularly common in Sheehan’s syndrome, which may be due to glucocorticoids deficiency coupled with increased AVP release as a consequence of reduced blood pressure and cardiac output resulting from glucocorticoid deficiency (32).

DIAGNOSIS

The basal pituitary hormonal levels and those after dynamic tests are beyond the purview of this chapter. However adrenal insufficiency is diagnosed with a morning cortisol level of 3 mcg/dl with low or inappropriately normal ACTH or a cosyntropin stimulated cortisol level <18 mcg/dl. Documentation of growth hormone deficiency does not require a dynamic test in presence of other pituitary hormone deficiencies. Only low age specific and assay specific IGF-1 assay may be sufficient to document adult growth hormone deficiency (AGHD) (34).

The preferred radiological imag­ing is an MRI of hypothalamic pituitary area.  CT scan may also be helpful. MRI findings in Sheehan’s syndrome usually vary with the stages of the disease. In earlier stages of the disease there may be an enlarged pituitary gland with central hypodensity (suggestive of infarction). However, an empty sella (complete or partial) is considered to be a characteristic of Sheehan’s syndrome in established cases (32).

TREATMENT

The acute adrenal crisis in Sheehan’s syndrome is treated with intravenous glucocorticoids. In other patients’ glucocorticoids should be started orally with hydrocortisone 15-25 mg daily in 2-3 divided doses with the higher dose in the morning and a lower dose in the evening (35). Mineralocorticoids are not necessary in general (35). Once daily prednisolone may also be used at a dose of 2.5-5 mg once daily in the early morning. As GH deficiency decreases cortisol clearance, it may necessary to increase the dose of glucocorticoid for those who receive GH treatment (35). Therapy is monitored with blood pressure, body weight, well-being, serum electrolytes, and blood glucose. Patients should be also be monitored for an overdose of glucocorticoids with weight gain, blood pressure, decreased bone mineral density, and other symptoms and signs of Cushing’s syndrome. All subjects with Sheehan’s syndrome should carry a ‘steroid card’ and should be advised strictly on how to increase the dose of glucocorticoid in stressful situation such as fever, infection, vomiting, trauma, etc.

Subjects with Sheehan’s syndrome should also be treated with levothyroxine, combined oral contraceptives according to guideline, calcium and vitamin D supplements, and growth hormone therapy (if possible) according to the protocol of adult growth hormone deficiency.

Viscerotropic Snake Bite

Snakebite is a major public health problem in tropical regions and is considered as one of the most neglected tropical diseases. The development of a Sheehan-like syndrome with chronic hypopituitarism following Russell viper envenomation is fairly common. Hypoadrenalism due to ACTH deficiency is the commonest abnormality (36). However acute hypopituitarism with predominant glucocorticoids deficiency has also been reported (37).

The venom of vipers is vasculotoxic in nature and the clinical features of viper venomation include local cellulitis and tissue necrosis, bleeding manifestations, disseminated intravascular coagulation, shock, and acute kidney injury (AKI) (38). Hypopituitarism is particularly common following vasculotoxic snake bite in subjects who develop AKI requiring hemodialysis. Hypopituitarism can develop as early as 7 days following snake bites and should be evaluated for particularly in younger subjects, especially those requiring increasing number of sessions of hemodialysis and in subjects with abnormal 20 min WBCT (whole blood clotting test) at presentation (36,39). On the other hand, the time of onset/presentation of hypopituitarism following snake bite may be as long as up to 24 years (40). Acute hypopituitarism is thought to occur due to acute damage to the pituitary gland at the time of the precipitating event, but a gradual/slower progression of pituitary damage may occur over years due to other unknown mechanisms (36).

Those who survive acute snake bite may later present with altered sensorium, loss of consciousness, seizure, shock, intractable vomiting, or more commonly with chronic complaints like asthenia and weakness, dizziness, anorexia, weight loss, nausea, vomiting and amenorrhea in females (36).

Variable degrees of hypopituitarism may be present. Cortisol deficiency is reported to be the commonest abnormality. Secondary adrenal insufficiency is diagnosed with a morning cortisol level of 3 mcg/dl with low or inappropriately normal ACTH or a co-syntropin stimulated cortisol level <18 mcg/dl (36). Documentation of growth hormone deficiency is done as mentioned in section of Sheehan’s Syndrome (34).

The preferred radiological imag­ing is the MRI of hypothalamic pituitary area which may show partial or complete empty sella or evidences of old hemorrhage. However, these changes are not present in all cases (41).

Treatment of secondary adrenal insufficiency and other hormone deficiencies are similar to described above. All subjects with hypopituitarism on glucocorticoids supplements should carry a ‘steroid card’ and should be advised on how to increase the dose of glucocorticoid in stressful situation such as fever, infection, vomiting, trauma, etc.

Thalassemia Major

Thalassemia’s are inherited autosomal recessive disorders of hemoglobin synthesis. Thalassemia major is the most severe form of beta thalassemia which involves the beta chain of hemoglobin. Organ dysfunction in thalassemia is principally attributed to excessive iron overload and suboptimal chelation. The precise underlying mechanism of iron overload induced organ dysfunction is not very unclear. The current management of thalassemia includes regular transfusion programs and chelation therapy. Pre-marital counselling and assessment with HPLC to assess the asymptomatic carrier has reduced its prevalence significantly in the developed world. However, this is still a major problem in many parts of the world.  Prevalence of adrenal insufficiency is variable and depends on the severity of iron overload. This secondary hemochromatosis can disrupt adrenal function by affecting the hypothalamic-pituitary-adrenal axis at the hypothalamic or pituitary level (42). In more severe cases primary adrenal failure may supervene due to iron deposition in the adrenal glands (42). Additionally, an extramedullary hematopoietic tumor has been reported in HbE thalassemia and beta thalassemia as non-hormone secretory unilateral or bilateral adrenal enlargement resembling adrenal myelolipoma (43). 

Biochemical adrenal insufficiency is reported to occur from   0% to 45% of subjects with thalassemia major (42), but adrenal crisis or clinical adrenal insufficiency is extremely uncommon and mostly they are asymptomatic. However, subclinical cortisol deficiency is not uncommon. In this context it should be remembered that mild symptoms of adrenal insufficiency like asthenia, weight loss, or postural drops are frequently overlooked as these features are common in thalassemia subjects with low levels of hemoglobin (42).                           

The unique finding in subjects with thalassemia is the dissociation between adrenal androgen levels with cortisol and aldosterone levels. This paradox is reflected by frequent documentation of low serum DHEA, DHEA-sulfate, androstenedione, and testosterone levels in the presence of normal serum cortisol and aldosterone levels (44). Absence of adrenarche occurring in most adolescents with thalassemia major is probably explained by this phenomenon (45). 

Diagnosis of adrenal dysfunction in thalassemia is similar to other causes of secondary adrenal insufficiency. If the morning cortisol is not unequivocally low, synacthen stimulation test should be done with either the low dose (1 µg) or the standard high dose (250 µg). A peak cortisol level of >18 µg/dL after 30-60 min of intravenous synacthen excludes adrenal insufficiency. Alternately an insulin tolerance test with a similar cut-off may also be done.

Treatment of clinical adrenal insufficiency is similar to that described above. Subjects with subclinical adrenal insufficiency require only steroid coverage during periods of stress.

HIV AND ADRENAL DYSFUNCTION

Endocrine manifestations of HIV infection may include adrenal dysfunction, hypothyroidism, hypogonadism, insulin resistance and diabetes etc. Changes in the HPA (hypothalamic-pituitary-adrenal) axis are the most frequent abnormality (46). Adrenal dysfunction in HIV infection may be a consequence of concomitant systemic illness, opportunistic infections, and neoplasm (47).

Probably the most frequent adrenal abnormality is a stress induced elevation in serum cortisol and ACTH (46). This may be due to activation of the HPA axis due to HIV infection itself or pro-inflammatory cytokines (e.g., IL-1β, IL-6 and TNF-α) (46). Alternately a peripheral increase in the conversion of cortisone to cortisol due to activation of 11-β HSD type 1 in adipose tissue or decrease in cortisol metabolism may be responsible for increased cortisol with subnormal ACTH (46). Tissue hypersensitivity to glucocorticoids is also reported in subjects with HIV-1 infection, which may result in hippocampal atrophy, altered secretion of cytokine/interleukins, etc. (48).

On the other hand, subclinical or clinical adrenal dysfunction can happen in about 10-20% of subjects with advanced disease and multiple co-morbidities when about 80-90% of the gland is destroyed (46). The involvement and destruction by HIV, opportunistic infections, or malignancies in the adrenal glands or the hypothalamus and/or pituitary area can result in either primary or secondary adrenal sufficiency (47).

The opportunistic infections include cytomegalovirus (CMV), Mycobacterium avium-intracellular and M. tuberculosis, fungal infections (such as Histoplasma, Cryptococcus, and Pneumocystis jirovecii), and Toxoplasma gondii (47). Of these opportunistic infections, CMV infection is known to be the commonest etiology with earlier literature reporting Cytomegalovirus adrenalitis in nearly 80 % of cases of HIV infection (46). However, due to improvements in active management of HIV by HAART (highly active anti- retroviral therapy), the prevalence of adrenal insufficiency has decreased over the last two decades.

Medications used for the treatment of HIV infection and its complication may also result in adrenal dysfunction. For example:  Rifampicin used for mycobacterial infection is a known hepatic Cytochrome P 450 (CYP) enzyme inducer and can lower serum cortisol levels by enhanced cortisol metabolism. Ketoconazole used to treat severe mycotic infections inhibits adrenal steroid synthesis and can lead to glucocorticoid deficiency or even adrenal crisis in patients with impaired adrenal reserve (49). Interestingly, ART-related lipodystrophy (dorsocervical fat pad enlargement and visceral adiposity) may mimic Cushing’s syndrome but it is typically not associated with hypercortisolism (49). On the contrary, some protease inhibitors (e.g., ritonavir) used in ART are reported to decrease metabolism of endogenous and exogenously co-administered glucocorticoids, resulting in an iatrogenic Cushing's syndrome.

Tumors of the adrenal gland in HIV infected patients include Kaposi’s sarcoma and high-grade non-Hodgkin’s lymphoma. Kaposi’s sarcoma is secondary to co-infection with the oncogenic human herpes virus type 8 (HHV8) and non-Hodgkin’s lymphoma could be secondary to Epstein-Barr virus (EBV).

Assessment for symptoms of adrenal involvement requires a high degree of suspicion as constitutional symptoms of HIV may mask the features of adrenal insufficiency.  Morning serum cortisol should be done in all cases suspected for adrenal dysfunction. Stress induced hypercortisolemia does not require any further testing and low serum cortisol <5 μg/dl with an elevated ACTH level requires treatment with glucocorticoids and mineralocorticoids. In other cases, synthacthen stimulated cortisol is used to determine the course of treatment. Stimulated cortisol <18 μg/dl, especially if associated with elevated plasma ACTH, should be treated as adrenal insufficiency. Asymptomatic subjects with stimulated serum cortisol <18 μg/dl should be advised to take stress doses of glucocorticoids only as mentioned before.

Diagnosis and management of adrenal disorders in a patient with HIV infection does not differ from that in immunocompetent persons in general.

ADRENAL HORMONE EXCESS SYNDROMES

Glucocorticoid Excess Syndromes 

The primary cause of Cushing’s syndrome, more common in tropical regions, is exogenous glucocorticoids. The background etiology for exogenous steroid usage includes: nephrotic syndrome, rheumatoid arthritis and other collagen vascular disease, bronchial asthma, Graves’ orbitopathy, etc.  Glucocorticoids used as inhalational agent for bronchial asthma, in creams and ointments for eczematous skin lesions may also be responsible. Endogenous steroid excess (Cushing’s disease, ectopic ACTH syndromes, adrenal tumors) are equally common in tropical regions as in other areas of the world.

Often it is a challenge to suspect exogenous glucocorticoid use based on the patient’s history, especially in situations when glucocorticoids were not being used for a therapeutic purpose. Subjects presenting with features suggestive of Cushing’s syndrome should therefore mandatorily undergo testing for basal morning cortisol (with paired ACTH if possible) to rule out exogenous glucocorticoid use. A suppressed morning cortisol and plasma ACTH strongly suggests the diagnosis (50). One important caveat is that prednisolone may cross react with some cortisol assays giving false positive results in some chemiluminescent assay (51). Additionally, if the patient is receiving hydrocortisone, the result will also be fallacious to interpret. It is not uncommon in tropical regions that some form of glucocorticoids is being used in disguise as an alternative medicine for joint pain, respiratory problems, fever, or even as a weight gain therapy for young lean subjects. Hence a more detailed evaluation of the history with leading questions and scrutiny of all past records of medicine, including that of the alternative medicines, may sometimes reveal the offending agent. 

The clinical features that suggest exogenous Cushing’s syndrome are lack of pigmentation and the absence of hypertension and hirsutism (as exogenous Cushing’s syndrome does not contain mineralocorticoids and androgens as opposed to endogenous Cushing’s syndrome). Patients with exogenous Cushing’s syndrome are prone to develop glaucoma, osteoporosis, psychiatric disturbances, etc. (50).

Once diagnosed, these subjects should be advised to withdraw the offending agents and should be given hydrocortisone in the lowest possible dose for preventing adrenal crisis. The withdrawal of hydrocortisone subsequently after 3 months depends on the morning cortisol, after stopping the previous evening dose and subjecting the patient to short synacthen test to assess the recovery of HPA axis. Those with morning cortisol between 5 -18 µ/dl should be advised stress coverage only. For bone protection, all subjects with exogenous Cushing’s syndrome should receive bisphosphonate therapy unless contraindicated (52). Adequate calcium supplements with cholecalciferol should also be used.

For subjects receiving glucocorticoids for therapeutic purpose, it is essential to maintain bone protection, check for secondary diabetes and hypertension, and prevent gastric ulceration. Withdrawal (if at all possible) should be performed very slowly. When the therapeutic steroid reaches the lowest possible dose to prevent crisis, it is converted to equivalent dose of hydrocortisone and the same principle is used as described before.

Licorice Induced Syndrome Of Apparent Mineralocorticoid Excess 

Licorice root extracts are used as a herbal medicine for several conditions like cough, peptic ulceration, etc. Licorice is also used as a sweetener and mouth freshener particularly in tropical regions (53). Licorice possesses some glucocorticoid activity, antiandrogen effect, estrogenic activity, and mineralocorticoid like activity. Subjects consuming excessive licorice may develop hypertension and hypokalemia (53). Sometimes this is severe enough to cause a cardiac arrhythmia. While screening for primary aldosteronism for subjects presenting with hypertension and hypokalemia, plasma aldosterone and plasma rennin activity are found to be suppressed in patients using licorice (53). 

                                                                                                                                                                           The active ingredient of liquorice is glycyrrhizic acid, which is hydrolyzed into glycyrrhetinic acid in vivo. Glycyrrhetinic acid has a very low affinity for the mineralocorticoid receptor but is a potent competitive inhibitor of the enzyme 11β-HSD type 2 which is preferentially expressed in kidney (54). Hence it may cause acquired 11β-HSD type 2 deficiency. The physiological role of the enzyme 11β-HSD type 2 is to inactivate cortisol to cortisone and thereby preventing access of cortisol to mineralocorticoid receptor. Cortisol and aldosterone have equipotent stimulating activity on mineralocorticoid receptor (54). Hence any situation associated with suppressed 11β-HSD type 2 activities may lead to overstimulation of mineralocorticoid receptors by cortisol, leading to hypertension with hypokalemia and metabolic alkalosis. After correction of hypokalemia, the screening test reveals suppressed aldosterone and plasma rennin activity (54). The hypertension is primarily due to sodium and water retention. A careful history for licorice ingestion clinches the diagnosis.

Treatment consists of avoidance of licorice products. In the interim period patients should be treated with oral potassium and spironolactone after the completion of screening of aldosterone rennin ratio (ARR). Withdrawal of licorice, even after prolonged use or ingestion of large amounts, leads to a complete resolution of the symptoms of acquired apparent mineralocorticoid excess (55).

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ABSTRACT

The converging epidemics of non-communicable disease like DM (DM) and an infectious disease like tuberculosis (TB) is a double burden. DM is increasing in the same population that is at high risk for developing TB. There is a two-to-four-fold higher risk of active TB in individuals with DM and up to 30% of individuals with TB are likely to have DM. Immune deficiency either in absolute or relative quantities are sufficient for re-activation of latent TB. From a 10% risk of reactivation over the whole lifetime of an immunocompetent individual, the risk of reactivation increases to 10% every year in immune-deficient individuals. DM impairs cell mediated immunity and poor glycemic control affects cytokine response and alters the defenses in the alveolar macrophages. Fever, hemoptysis, extensive parenchymal lesions, and lung cavities are more common in those with DM particularly heavier and older males. DM increases the risk of treatment failure, death, and relapse. Evidence collected from meta-analysis conclude that DM can increase the odds of developing Multi Drug resistant TB (MDR-TB). The synergism between DM and TB necessitates bi-directional screening. Sputum examination for Ziehl-Neelsen staining is both a sensitive and specific screening test. Rapid molecular diagnostic tests like cartridge based nucleic acid amplification tests (CB-NAAT) are useful in cases where there is a high-index of suspicion and difficulty in arriving at a definitive diagnosis exists. Random plasma glucose and HbA1c (glycosylated Hemoglobin) measurements are convenient tests for DM screening that can be done in non-fasting individuals. Screening for DM more than once during the course of illness is sensible so that transient DM and new-onset DM can be identified. Anti-TB drugs affect glycemic control as they interact with anti-diabetic drugs by either stimulating or inhibiting the metabolizing enzymes. They may also aggravate metabolic, ocular, and neuropathic complications of DM. Insulin is the preferred drug in most instances. The presence of renal and hepatic dysfunction affects TB and hyperglycemic management.

INTRODUCTION

Tuberculosis (TB) and diabetes mellitus (DM) are two diverse conditions of immense public health importance existing for centuries. TB was traditionally identified with poverty while DM was considered as an entity associated with prosperity. TB is today one of the commonest and widespread communicable infectious diseases largely but not necessarily confined to low-economic groups. DM on the other hand spearheads the group of chronic non-communicable diseases affecting people across all socio-economic strata. Contrary to previous beliefs, a larger number of people with DM are living in middle- and low-income countries. Unfortunately, these are the countries where DM is expected to increase in the near future (1). Both DM and TB have been associated with significant morbidity and mortality from time immemorial. Advancements in modern medical science over the years has definitely improved the outcome in both these conditions. But the magnitude of these two diseases has not waned and both are collaborative in worsening each other. In fact, the increase in the population affected with DM is sustaining the TB epidemic.

TB is associated with the endocrine system in different ways. The effects of TB on the endocrine system are discussed in detail in another Endotext chapter (2).  The interaction of TB and DM is discussed in this chapter.

TUBERCULOSIS

TB is a global health threat, particularly to the poor and the susceptible. It is estimated that on average approximately 9 to 10 million people are affected by TB and around 1 to 2 million succumb to it annually (3). In 2019, 1.3 million people died due to TB. In developed countries, TB has slipped down in ranking among the global list of top 10 diseases causing mortality. However, in the underdeveloped regions it still remains among the top 10 diseases with high mortality (up to 30%). When in concurrence with retroviral infections, the risk of active TB is 12 to 20 times higher and the mortality is higher even in developed countries (4). Multi drug resistant TB is another rising problem which requires expensive second line drugs and a longer duration of treatment. A large proportion of the global population is at risk and the true prevalence and the annual incidence also depends on access to health care facilities and the laboratory-based testing capacity of the regions. Individuals who are in close contact with affected individuals, people living in crowded places, immigration to a country or area with a high prevalence of TB, and children less than 5 years of age are considered vulnerable to getting infected by the TB bacilli (Table 1). Bacillary load in the sputum of the infectious individual and close proximity to the infectious persons are two important external determinants for infection in any individual after exposure.

Latent Tuberculosis

In most of the exposed individuals the infection is quelled by the immune system and the bacilli are fenced inside a granuloma or tubercle, immunologically aborting an active disease. This is a subclinical disease (LTBI – Latent TB infection) which doesn’t have symptoms and can last for weeks or decades. This latent infection is seen in nearly one third of the world population. Even though non-infectious, they carry the risk (about 10%) of re-activation into active TB later (primary progressive TB) (5). Such re-activation occurs in immunocompromised as in HIV infection, those on immunosuppressive agents (such as post organ transplant, autoimmune diseases, and allergic diseases), conditions like DM, alcoholism, substance abuse, silicosis, malnutrition, steroid therapy, renal failure, malignancies, indoor air pollution, and smoking. The World Health Organization (WHO) has guidelines on the approach to latent TB especially in countries where the burden of TB is low (an incidence of < 100 / 1, 00,000 per year). It strongly recommends screening and treatment of latent TB in high-risk individuals in these countries (6).

TB is an airborne infectious disease which spreads by droplets. TB affects the lungs primarily (Pulmonary TB) and when it affects the pleura, bones/joints, abdominal organs, lymph nodes, and meninges it is called extra-pulmonary TB. Mycobacterium tuberculosis, the causative agent has a thick mycolic acid cell wall that enables its survival in the environment and in its host. External to its cell membrane it has a peptidoglycan polymer which makes it impermeable. Its cell wall also contains lipoarabinomannan which enables its phagocytosis by macrophages and facilitates its survival inside macrophages in airways especially alveoli (7). The ability of the host’s defense system then determines whether the outcome is a progressive primary pulmonary disease or a latent state.

DIABETES MELLITUS

The prevalence of DM is rapidly increasing to justify it to be termed as an epidemic disease. According to WHO, the global prevalence of DM has doubled from 4.7 % in 1980 to 8.5% in 2014 (8). From an estimated prevalence of 463 million in 2019, it is estimated to increase to 578 million in 2030, and 700 million in 2045. For every diagnosed individual with DM there is another undiagnosed person with DM (9). The differences in the prevalence of DM between high and middle-income countries and similarly between rural and urban population are decreasing.

According to WHO, non-communicable diseases constitute 7 out of the top 10 leading causes of death and DM is prominent among them. In 2019 the estimated number of deaths to have occurred due to DM globally is approximately 4 million (10). DM is associated with significant morbidity due to its microvascular and macrovascular complications and high cardiovascular mortality. DM is a major cause of cardiac ischemia, stroke, renal failure, blindness, and amputations.

THE DIABETES-TUBERCULOSIS EPIDEMIOLOGY: THE BIDIRECTIONAL LINK                          

The high prevalence of DM and TB being in epidemic proportions has rightly earned them the names ‘the converging epidemics’ and ‘double burden’ (11,12). Due to rapid changes in lifestyle, urbanization, and epidemiological changes, DM is increasingly seen in low- and medium-income groups, and in younger individuals more frequently than before. The prevalence of DM is increasing faster where TB is endemic already. Unfortunately, these are the regions in the world where health care facilities are less common. According to International Diabetes Federation, the 50-55% increase in the prevalence of DM over the next 2 decades will occur predominantly in the continent of Africa (10). A longitudinal, multi-national study involving low-income countries concluded that an odds ratio of 4.7 for prevalence and 8.1 for incidence of TB is highly likely in those counties where DM has increased over the last decade (13). The WHO states that younger age group individuals are three times more likely to get infected with TB (14). There is a two-to four-fold higher risk of active TB in individuals with DM compared to non-diabetic individuals (15). According to a meta-analysis by Wilkinson et al, around 4 % of people with type 2 DM develop TB (16). Since the number of individuals with undiagnosed DM in the world is expected to be more than 50%, the proportion of TB in DM also should be much higher. Analytical models that try to project the future burden of TB in DM predict that the increase in DM counteracts the decreasing incidence of TB by at least 3% over the next 15 years (17).

Increased chances of finding undetected and uncontrolled hyperglycemia in close household contacts of subjects with TB have been mentioned in studies from Asian counties. In fact, a systemic analysis of a group of heterogenous studies on bi-directional screening i.e., screening for TB in DM affected individuals and vice versa has shown some evidence to support active screening for both DM and TB in the affected individuals and family members (18). Up to 35% of TB patients may have DM and the quoted figures are variable in literature (19). Jean Jacques Noubiap et al in their systematic review and meta-analysis of data from 2.3 million people with TB world-wide estimated that the prevalence of DM in patients with TB is around 15 % and was twice that of the general population (20). These data clearly give epidemiological evidence for the co-existence of DM and TB as a syndemic. A potentially lethal combination of a communicable disease and a non-communicable disease having a synergistic effect is a challenge on the public health system.

Epidemiology of Diabetes Among Patients with Active Tuberculosis

The WHO collaborative framework recommends for a joint plan for DM and TB related activities which have to be reflected in the national plans on non-communicable diseases and TB respectively (21). As per the WHO approximately15% of TB cases in the world are associated with DM. Of these 15%, India accounts for more than 40% of the cases (19). Estimates of the burden of DM and TB co-existence has primarily come from studies looking at prevalence of DM and glucose intolerance among newly diagnosed patients with TB diagnosed in TB clinics. The community prevalence of these two disorders co-existing are not clear. Many of these studies have been done in hospitals where sicker patients with TB are treated which would probably account for a higher percentage of patients having glucose intolerance and DM. In a study from five randomly selected TB care clinics in the southern state of Tamil Nadu, around 25% of patients with TB had coexisting DM. Around 10% of these patients had newly diagnosed DM. Risk factors for having DM in this group of patients included older age, higher basal metabolic index (BMI), family history of DM among first degree relatives, and following a sedentary lifestyle (22). Close to Tamil Nadu in the southern state of Kerala, the prevalence of DM in patients with TB was nearly double that observed in the previous study. Among the patients with TB in Kerala, 44% had DM. Among them about half (21%) had newly diagnosed DM (23). The risk of DM was higher among those with sputum positive TB in both of these studies. In a study from Odisha on the Eastern part of India, 13.9% of tribal patients with TB had DM suggestive of a significant burden of disease even among poorer regions of the country (24). In a retrospective study, among 1000 patients with TB from the northern state of Punjab, 11.6% had DM and TB coexistence (25). In the same state the authors found 30% of patients with TB diagnosed in a tertiary referral hospital had DM (26).

To better understand the prevalence of DM among newly diagnosed patients with TB a large multicentric study involving five centers is in progress (GIANT Study - Glucose Intolerance Among New patients with TB - Clinical Trial Registry India - CTRI/2019/05/019396). This study incorporates simultaneous OGTT and HbA1c determinations at three different time points to ascertain if HbA1c can replace the standard oral glucose tolerance test (OGTT) in this population and avoid the inconvenience of performing an OGTT.

A recent systemic review and meta-analysis ascertained the worldwide prevalence of DM among active cases of TB. This meta-analysis involved over 200 studies that included a little under 2.3 million patients with active TB. The overall pooled prevalence was similar to the WHO estimate of 15% prevalence of DM in patients with active TB. However, this varied from 0.1% in Latvia to 45% in the Marshall Islands. The high prevalence areas as per the International Diabetes Federation included North America, Western Pacific (which includes Australia and China), South East Asia, North Africa, and Middle East Asia (27). Figure 1 summarizes the information on the prevalence of DM and active TB in 7 regions of the world.

Figure 1. Prevalence of DM among patients with active TB in the seven International Diabetes Federation (IDF) regions of the world. The areas in red have the high burden of DM co-existing with active TB. The low burden areas are marked in blue. (adapted from ref 27)

Chronic hyperglycemia impairs immunity (both innate and adaptive). DM impairs cell mediated immunity and poor glycemic control affects cytokine response and alters the defenses in the alveolar macrophages. Hyperglycemia disrupts the recruitment of neutrophils, chemotactic movement of monocytes, and phagocytic action of alveolar macrophages. Also, the antigen-specific interferon-gamma release is affected as the T-helper cell activation is ineffective. In addition, altered pulmonary microvasculature and micronutrient deficiency facilitate the invasion and establishment of TB as surveillance and nutrition is compromised. The chronic immunosuppression or ineffective immune response predisposes the individual for TB infection and with a higher bacilli load. This is summarized in Figure 2.

Figure 2. DM is associated with increase in active TB and relapse in TB which both may be a result of the direct effect of diabetes. There is increased death in DM and TB which may be secondary to TB or due to the inherent excess mortality of DM due to cardiovascular disease

CLINICAL PRESENTATION

 

The manifestations of tuberculous infection in patients with DM have been documented to be different from those without diabetes. Fever and hemoptysis in diabetic population is more common compared to the general population. Radiographic differences include higher than usual parenchymal lesions and lung cavities (30). There are reports of a higher incidence of lower lobe involvement in individuals with DM in contrast to the classical upper lobe involvement in the general population. Also, a higher rate of other atypical presentations like a reduced rate of sputum conversion (low quality evidence), higher probability of treatment failure and death (moderate quality evidences) is known to occur when DM occurs with TB. A higher rate of recurrence and reactivation of latent TB infection (OR=1.83) has been documented (31). Subjects affected with TB and DM are found to be heavier and older males compared to those without diabetes. More pulmonary than extra-pulmonary involvement is seen in TB with DM (32).

 

Outcome

 

Negative smear or culture on two separate occasions while on treatment and on completion of treatment defines a cured TB (Table 2). Apart from being a risk factor for increased incidence of active TB, co-existence of DM worsens the outcome even in treated patients. In the pre-insulin era, the commonest cause of death in DM apart from diabetic coma was the co-affection with TB (33). DM increases the risk of treatment failure, death and relapse. The risks are likely to be an underestimation as loss of follow-up or unreported death has been a major problem in data collection on outcome in TB management. In a systematic review and meta-analysis by Baker et al, the risk ratio for combined treatment failure and death was 1.69. The risk ratio for death was 1.89 when unadjusted and went up to 4.95 when adjusted for age and other confounding factors.

 

Table 2. Terminology and Definitions
Terminology	Definitions
Treatment completed	Bacteriologically confirmed TB patient who has completed treatment without evidence of failure, but not yet completed sputum test to prove negative result in the last month of treatment and on at least one previous occasion
Cured	Bacteriologically confirmed TB in whom smear- or culture-was negative in the last month of treatment and on at least one previous occasion
Treatment Success	The sum of cured and treatment completed
Treatment Failed	Sputum smear or culture positive at or beyond 5th month of treatment
Died	A proven patient who dies for any reason before or during the course of treatment
Lost to follow-up	A proven patient who did not start treatment or who has interrupted treatment for 2 or more consecutive months
Not Evaluated	A proven patient for whom no treatment outcome is assigned. Includes cases “transferred out” to another treatment unit as well as cases for which the treatment outcome is unknown to the reporting unit

Terminology and Definitions adopted from RNTCP, Revised National TB Control Programme, Training Course for Programme Manager (Modules 1-4), 2011.Training modules. Central TB Division. https://tbcindia.gov.in.

 

The risk ratio for relapse was 3.89 but no additional risk of TB relapse in those with multidrug resistant TB was demonstrated. In their analysis, Baker et al found that the effect of co-existing DM on sputum conversion 2 to 3 months after treatment was variable (0.79 to 3.25) and wide (34). Persistence of sputum positivity i.e., delay in sputum conversion has been shown in a few studies. The authors conclude that advancing age and underlying co-morbidity contribute to death and is not due to drug resistant TB or severity of hyperglycemia (35).

 

BI-DIRECTIONAL SCREENING FOR DIABETES AND TUBERCULOSIS

 

The synergism between DM and TB in terms of epidemiology and outcome necessitates bi-directional screening for the presence of either TB or DM in the presence of the other disorder. The Collaborative Framework for Care and Control of TB and DM proposed by the World Health Organization (WHO) along with the International Union against TB and Lung is an effort towards bi-directional screening and management of both these conditions (36). Studies implementing bi-directional screening point towards its feasibility and effectiveness (18).

 

Screening for Active TB Among Patients with Diabetes

 

The diagnosis and treatment of TB is affected by substantial delay which occurs at multiple levels a) between the onset of symptoms and clinical presentation b) clinical presentation and suspicion of TB c) Clinical suspicion of TB and its confirmation. This is due to variability in symptoms, host immunity, lack of knowledge, paucity of access to medical care, and lack of rapid and reliable diagnostic tools. The average delay even in resource- rich countries after presentation to heath care system is 3 weeks (37). According to WHO, patients with suspected TB should be promptly sent to TB diagnostic and treatment centers and evaluated accordingly.

 

The higher risk of TB in diabetic population compels intensive screening for detection of TB at the earliest time so as to reduce transmission, morbidity, and mortality. WHO recommends for TB surveillance among patients with DM in settings with medium to high TB burdens. The practical difficulties are the non-availability of TB screening tools in all DM clinics. Also, in areas of low TB burden, the cost-effectiveness is low. The number needed to screen to detect one case of active TB depends on the prevalence in that area. Screening of all patients with clinical history during their visit to diabetic clinic and additional testing in symptomatic and high-risk patients should be undertaken. Also screening for TB whenever there is unexplained worsening of metabolic control would help detect occult cases. Different modalities (clinical, radiological, sputum microbiology) alone or in combination are used for screening individuals with DM for the presence of active TB.

 

Clinical Assessment

 

It is inexpensive and requires minimum time. Fever, cough of more than 2 weeks duration, hemoptysis, weight loss, night sweats, and exposure to a case of active TB are the clinical clues to suspect pulmonary TB. Lymphadenopathy, fever with altered sensorium, neck stiffness, abdominal symptoms like ascites, intestinal obstruction etc. all favor the possibilities of extra-pulmonary TB. But clinical symptoms lack both sensitivity and specificity as it excludes asymptomatic patients and relies on the presence of symptoms.

 

Radiography of the Chest

 

It has good sensitivity to pick up asymptomatic pulmonary cases, but there can be false positive results. Inconsistent evidence exists on the presence of atypical findings of TB in the chest x-rays of individuals with diabetes. The presence of clinical symptoms of fever, cough, hemoptysis, and weight loss with an abnormal chest-x-ray helps in the presumptive diagnosis of TB. Figure 3, 4, and 5 show different radiological presentations of pulmonary TB.

Figure 3. Chest Radiographs suggesting fibrocavitatory lesions. Post primary infections and reactivation of pulmonary TB are more likely to cavitate. They are most common in the posterior segments of the upper lobes (85%) as seen in Picture A. Red arrow pointing to the cavity. The other common site is the superior segment of the lower lobe (Picture B) Yellow arrow pointing to the cavity (Picture courtesy- Prof Mary John, Christian Medical College and Hospital, Ludhiana)

Figure 4. Chest Radiographs suggesting lobar consolidation. (Picture courtesy- Prof Mary John& Dr Neeru Mittal, Christian Medical College and Hospital, Ludhiana)

Figure 5. Chest Radiographs suggesting miliary TB. It represents hematogenous dissemination of an uncontrolled tuberculous infection. Although implants are seen throughout the body, the lungs are usually the easiest location to image. Miliary deposits appear as 1-3 mm diameter nodules uniformly distributed in the lung parenchyma. (Picture courtesy- Prof Mary John & Dr Neeru Mittal, Christian Medical College and Hospital, Ludhiana)

Microscopic Examination 

 

Sputum collected for Ziehl-Neelsen staining and examination for acid -fast bacilli is both sensitive and specific. Even-though they are the commonly used confirmatory tests, most diabetes-oriented clinics are unlikely to have standard laboratory facilities for sputum tests even though having a radiography unit for screening TB appears feasible (32). Sputum tests have limitations in cases of scanty sputum or salivary contamination especially in children. If sputum availability is scanty then sputum is induced by saline nebulization, which if not helpful, can be followed by bronchoscopy assisted lavage or trans-bronchial pulmonary biopsy.

 

Sputum Culture

 

The gold standard test is sputum culture for TB bacilli but is both time consuming (turnaround time 8 weeks) and expensive. It cannot be used for all individuals attending the DM clinic and is reserved for those patients where the index of suspicion is high and in difficult cases when other available tests are not contributory for diagnosis. Sputum culture is also useful for assessing response in multi-drug resistant TB.

 

Rapid Molecular Diagnostic Tests

 

Tests like cartridge based nucleic acid amplification test (CB-NAAT) (Figure 6) or rapid automated molecular test Expert MTB/ RIF assay using polymerase chain reaction have a quick turnaround time of two hours and additional advantage of using a single sputum sample. They also detect the presence of rifampicin resistance. Being expensive it cannot be used for screening all patients with DM even though it has high sensitivity and specificity. But they are useful in cases with high-index of suspicion and difficulty in arriving at a definitive diagnosis.

Figure 6. All district hospitals in India have been provided with Cartridge Based-Nucleic Acid Amplification Testing equipment under the RNTPC program. Picture of the equipment at Civil Hospital, Ludhiana (Picture courtesy- Dr Ashish Chawla, Civil Hospital, Ludhiana)

Screening for Latent TB Among Patients with Diabetes

 

As mentioned earlier, Identification and treatment of latent TB infection to prevent its progression to active disease is necessary to prevent morbidity, mortality, and spread of TB. The WHO AND USPSTF (US preventive services task force) have issued strong guidelines for the screening and treatment of latent TB infection in high risk adults aged more than 18 years in countries with low incidence of TB (38,39).The high risk groups include persons hailing from countries with high TB prevalence, persons residing in homeless shelters and correctional facilities, immunocompromised individuals (HIV, those on immunosuppressants including post-organ transplant), silicosis, those receiving dialysis, those receiving anti-TNF-alfa inhibitor treatment, previously treated TB, and persons who come in contact with those active TB (household contacts and health care workers). The Mantoux tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are the two screening tests used and they are moderately sensitive and highly specific (40,41). In the tuberculin test, purified protein derivative (PPD) is injected intradermally and assessed within 48 to 72 hours for the presence of induration which is a palpable hard swelling (a diameter of more than 10 mm is considered positive) over the injected area (42,43). In the IGRA a single venous blood sample is taken for the assay and the reports are available within a day. They are particularly useful in those who are unlikely to return for TST test reading and BCG vaccinees.

 

There is no consensus on the issue of screening for latent TB infection in DM as a high-risk group. The results of studies done previously have been inconsistent. Studies have shown a variable prevalence of latent TB infection and there are no randomized controlled trials demonstrating the benefits of screening. Similarly, there are no recommendations for chemoprophylaxis of latent TB infection in individuals with DM due to the lack of randomized controlled trials that show benefit. The small added risk of hepatotoxicity with chemoprophylactic drugs given for TB in latent TB infection has been the only concern arguing against such measures.

 

Screening for Diabetes in Tuberculosis

 

In geographical regions with a high prevalence of diabetes, screening for hyperglycemia in TB affected individuals is highly recommended (14). Detection and monitoring of hyperglycemia is an essential part of infection management in any patient with an infectious disease. Chronic infectious diseases like TB thrive in hyperglycemic individuals and the outcome is unfavorable in a hyperglycemic milieu. Recognition of hyperglycemia during the entire course of the illness in TB affected individuals implies either monitoring of pre-existing hyperglycemia or new onset of transient or permanent hyperglycemia. Transient hyperglycemia is a manifestation secondary to the insulin resistance induced by the inflammation of TB infection. There is evidence that hyperglycemic status improves during the course of anti-TB treatment. The optimal time to screen for DM in TB patients on anti-TB treatment is thus unresolved particularly when it is well known that transient hyperglycemia exists during the course of TB. Many groups have advocated for screening more than once during the course of illness i.e., once at the initiation of treatment and at least once again either during and at the time of completion of TB treatment.

 

In regions with high prevalence of diabetes, younger age of onset of DM is on the rise and this is an emerging problem. There is a three times higher risk for younger individuals to get TB and a two-to four-fold higher risk in diabetic individuals compared to non-diabetic individuals. Hence screening for DM in all individuals 18 years of age or older appears logical.

 

The type of tests for screening patients with TB for DM depends on the availability of the local health care facilities, cost of the tests, and the ability of patients to come back for additional or repeat tests. Symptom based screening for DM has a low sensitivity. Risk score-based screening also is marred by low sensitivity and specificity. Random plasma glucose test and HbA1c (glycosylated Hb) are convenient tests that can be done in non-fasting individuals as screening tests. Glycosylated Hb test which doesn’t require a fasting blood sample helps to differentiate stress induced hyperglycemia from spontaneous onset pre-existing diabetes. Oral glucose tolerance test (OGTT) with 75 gm helps in identifying impaired glucose tolerance (IGT) and frank DM. A FBG ≥126 mg/dL or random plasma glucose ≥200 mg/dl on two tests is diagnostic of diabetes; FBG 110to 125 mg/dL is considered as impaired fasting glucose and post glucose values between 141- to 199 mg/dl is taken as impaired glucose tolerance (43,44). In one study, the number of TB patients needed to screen (NNS) for detecting DM was on average 40. But in the same population it was lower among smear positive subjects (NNS = 23), in age less than 40 years (< 40 years vs. > 40 years NNS = 35 Vs 47), in males (male vs. female NNS = 31 vs. 116), smokers (smoker vs. non-smoker NNS = 27 vs. 68) and HIV positive (Positive vs. Negative 22 Vs 43) indicating that there are high risk individuals (46).

 

Currently, screening for DM in individuals with TB and screening for TB in patients with DM where the prevalence is > 100/1,00,000 population appears feasible. Once diagnosed as having diabetes, diet and drug therapy is initiated and the patients are followed up closely for assessing the glycemic response. Transient hyperglycemic situations improve either spontaneously or with minimal medical intervention. After completion of TB medications, regular follow-up with glycemic monitoring is recommended for all patients who had diabetes.

 

MANAGEMENT OF DIABETES AND TUBERCULOSIS 

 

Anti-Tuberculosis Therapy in Diabetes

 

Management of DM should be according to the existing global guidelines with adaptations according to the regional needs. The treatment of TB in DM is not different from the general population. DOTs (Directly Observed Treatment, short-course) is a patient-centered WHO strategy adopted to treat individuals with active TB. A trained health worker provides drugs and observes in-person the patient taking the drug. It guarantees compliance, completion of the treatment course and prevents transmission, treatment failure and development of drug resistance. For newly detected TB, 2 months of intensive phase with 4 drugs (INH, Rifampicin, Pyrazinamide and Ethambutol) and 4 months of continuation phase with 3 drugs (except pyrazinamide) is the standard regimen. For those with a relapse 3 months of intensive therapy with 5 drugs (streptomycin in addition) followed by 4 months of continuation phase with 3 drugs (except pyrazinamide and streptomycin) is administrated.

 

In Chronic Kidney Disease

 

All four first line drugs (RIF, INH, PZA and EMB) can be used in patients with CKD. Up to 50% dose reduction for EMB and PZA may be needed in patients with creatinine clearance <10 ml/min. Regular monitoring is advised to ensure optimal therapy.

 

Adverse Effects of Anti-TB Drugs

 

INH induced peripheral neuropathy may worsen the underlying diabetic neuropathy. Pyridoxine is supplemented to prevent this. INH is also associated with hepatitis. Ethambutol is known to produce optic nerve toxicity which may confound diabetic retinopathy. Also, ethambutol and rifampicin are known to affect the kidneys. Rifampicin can induce immune-allergic reactions. Pyrazinamide is rarely associated with liver injury but its more common side effect is hyperuricemia induced joint pain. Streptomycin is potentially associated with renal and cochleo-vestibular toxicity

 

Multi-Drug Resistant TB (MDR-TB)

 

Multi-drug resistant TB (MDR-TB) is an added medical and economical burden as it is much more difficult to treat, involves therapy with atypical anti-TB drugs for a longer duration of time, and requires referral to specialty centers. Infections caused by mycobacterial strains which are resistant to INH and rifampicin are called multi-drug resistant TB infections. If there is additional resistance to one fluroquinolone and one of the additional inject able drugs (Kanamycin, Capreomycin or Amikacin) then it is called extensive drug resistant TB (XDR-TB). It is associated with poor outcomes and risk of continued transmission (47). Treatment outcome always has been poor due to the complex drug regimen, non-availability of all the drugs, and the possible occurrence of XDR-TB. The reason for resistance is multi-factorial including patient’s non-compliance to therapy, incomplete or inadequate treatment of susceptible TB, decision error by the treating community, etc. Resistance to drugs arises from mutations which are spontaneous and restricted to specific gene loci making it detectable without much difficulty.

 

There is inconsistent data on the incidence of TB-drug resistance in diabetes. Tegegne et al in their meta-analysis concluded that DM can increase the odds of developing MDR-TB.  (47,48). Observational studies have shown delayed clearance of mycobacterium, failure of treatment, relapse and death in the presence of DM (49). The possible theoretical explanations pertaining to the influence of DM in developing resistance include lower drug concentrations, hyperglycemia induced acute and chronic effects of immune regulation, and the presence of more extensive disease in DM affected individuals (50).

 

Altered plasma concentrations of the anti-TB drug rifampicin has been demonstrated in the continuation phase (but not in the induction phase) of TB treatment in individuals with DM (51). The heavier body weight of insulin resistant individuals with DM is supposed to be one of the reasons because of the use of fixed-dose combination drugs. Giving an exact weight-based dose for a longer duration of time is suggested to overcome this hurdle (52). In addition, DM can influence the plasma concentrations of anti-TB drugs. The absorption, distribution, and metabolism of anti-TB drugs may be altered either due to local gastrointestinal causes (gastropathy, polypharmacy mediated interactions) or dysautonomia of DM predisposing to treatment failure.

 

After initiation of treatment all patients should be closely followed for evidence of resistance. Persistent sputum positivity at the end of 2-3 months of ATT therapy should prompt a look for evidence of drug resistance. CT chest features have been demonstrated to be different from non-DM subjects. Pulmonary segment consolidation and lobe consolidation seen as moth-eaten cavities without a wall and filled with fluid are the features mentioned in published data. They are accompanied by bronchial damage (53). Multiple moth-eaten cavities in chest CT while on ATT should prompt the suspicion of MDR-TB. Rapid molecular techniques like CB-NAAT or sputum culture for sensitivity should be used to look for drug resistance. All MDR-TB should be referred to specialized centers dealing with MDR-TB.

 

Drug Therapy in Multi-Drug Resistant Tuberculosis

 

The second line drugs are generally less efficacious and more toxic. In the presence of drug resistance second line agents are used in multiple combinations to address different pharmacological targets in the mycobacterium. In addition to one of the first line drugs to which there is retained susceptibility, an injectable agent, a fluroquinolone and class 4 and class 5 drugs are used in combination to combat MDR-TB (53). Bedaquiline and Delamanidare are new anti-TB drugs used in MDR-TB

 

Bedaquiline belongs to the diarylquinoline group. It inhibits mycobacterial ATP-synthase activity. A shorter time to sputum conversion compared to placebo has been demonstrated. The adverse effects include enzyme induction,electrolyte imbalance, QTc prolongation, and gastrointestinal toxicity (54).

 

Delamanid a dihydro-imidazooxazole that inhibits mycolic acid synthesis also has shown a shorter time period taken for sputum conversion while used in the regimen for MDR-TB. A dose dependent association with QT prolongation occurs (55).

 

Linezolid an oxazolidinone has demonstrated 87% sputum conversion but more than 80% of patients had adverse effects. Peripheral neuropathy, myelosuppression, optic neuropathy, and rhabdomyolysis have been documented in study subjects.

 

ANTI-DIABETES THERAPY IN TUBERCULOSIS    

 

The outcome of TB in DM is also dependent on good glycemic control. The management of hyperglycemia in TB depends on many factors like age, duration of diabetes, presence of complications of DM and co-morbidities, existing drugs, patient support and preferences, economic background and access to medical facilities.

 

Changes in the lifestyle pattern is once again reiterated when starting ATT. Adequate nutrition with high quality protein without affecting glycemic control is the corner stone of managing nutrition associated glycemic status in TB. In the presence of nephropathy or liver disease, the protein intake has to be modified appropriately and spurious use of protein is avoided. Vitamins particularly pyridoxine (B6), methylcobalamine (B12), vitamin A and Vitamin D should be adequately replaced. Tobacco use and alcohol consumptions have to be stopped. Moderate intensity exercise can help weight lose and improve glycemic control in overweight individuals.

 

Drug regimen, monitoring and follow-up should be individualized to maximize benefit with minimal discomfort and side effects like hypoglycemia, arrhythmias etc. Monitoring of capillary blood glucose at home, dose adjustment, monitoring of renal and liver functions are required during follow-up.

 

Anti-TB drugs can influence the metabolism of anti-diabetic medications (Table 3). Rifampicin, by cytochrome p450 enzyme induction, increases the metabolism of most oral anti-diabetic drugs, which may worsen the hyperglycemia. INH on the other hand inhibits cytochrome P450 enzymes and prolongs the effect of anti-diabetic drugs.

 

Table 3. Anti TB Drugs and Drug Metabolism (Ref 57-59)
Anti TB drug	Effect on Cytochrome P 450	Effect on anti- diabetic drugs
Rifampicin	Induces the cytochrome enzymes thereby accelerating the elimination of drugs like sulphonylureas, thiazolidinediones, and meglitinides	Reduced effect of sulphonylureas by one-third due to CYP2C-mediated accelerated metabolism leading to hyperglycemia   Reduced effect of thiazolidinedione by half due to CYP2C8-mediated accelerated metabolism leading to hyperglycemia
INH	Inhibits	Reduced elimination through action on CYP2C9; persistent effect and risk of hypoglycemia
Bedaquiline	Enzyme inducer	Can reduce the effect of anti- diabetic drugs

 

Aggressive therapy of DM is necessary for optimal response to TB therapy (Table 4). Insulin is the drug of choice in most illnesses including TB; insulin has the advantage of producing an anabolic effect, positive influence on appetite, and faster relief of hyperglycemic symptoms. It is the most suitable anti-hyperglycemic agent in cachexic and low BMI individuals. It is a mandatory therapeutic agent in Type 1 diabetes, pancreatic diabetes, severe DM and TB, coexisting renal or hepatic diseases, situations complicated by drug interactions and oral drug intolerance. Insulin is neutral in drug-to-drug interactions and achieves glycemic control faster than oral drugs. In the presence of fasting hyperglycemia of > 200 with ketonuria, Insulin is used to treat the hyperglycemia. It is also the preferred drug in renal impairment. The main disadvantage with insulin is that it has to be injected and more than twice a day in presence of infection/ stress. The indications for insulin use in patients with active TB and DM is summarized in Figure 7.

Figure 7. Indications of Insulin Use in patients with Type 2 DM and Active TB

Metformin has the advantage of not producing hypoglycemia when used alone. It can however reduce appetite and needs caution while being used in renal or hepatic dysfunction. It doesn’t interact much with ATT and doesn’t influence cytochrome enzyme induced metabolism. It can help to shorten the course of TB therapy. It modifies the immune response and inflammation. It acts on the mitochondrial respiratory chain and can reduce the intracellular growth by acting through AMPK pathway which has a negative impact on the inflammatory process.

 

Table 4. Anti-Diabetic Drug Use in Patients with Tuberculosis
Drug	Advantages	Disadvantages	Comment
Insulin	Increases appetite, weight; anabolic effect; No drug interactions with ATT	Injectable   Needs supervision for change in requirement	Preferred in lean diabetes, secondary diabetes, severe DM with ketosis or hyperosmolar state
Metformin	Oral; Cost-effective and easily available Not influenced by ATT; positive anti-TB adjuvant action	Gastrointestinal disturbances; Needs renal and hepatic function monitoring; Change in eGFR (< 35 ml/ min/l) or > 3 times raised liver enzymes necessitates stopping metformin; Not suitable in hypoperfusion states (risk of lactic acidosis)	Not potent in severe hyperglycemic situations. Can be used in mild forms of hyperglycemia.
Sulphonylureas	Quick restoration of euglycemia	Long-acting drugs can induce hypoglycemia in anorexic people	Shorter acting sulphonylureas such as gliclazide and glipizide
DPP4- inhibitors	Less hypoglycemic potential	? Risk of immune dysregulation – respiratory Infection	Selective use
Alpha glucosidase inhibitors	No hypoglycemia	GI intolerance	In mild post meal elevation
Thiazolidinediones	Against insulin resistance	Hepatic	Selective use
SGLT2 inhibitors	No hypoglycemia	Dehydration, DKA	Selective use

 

Metformin increases the host cell production of reactive oxygen species and acidification of mycobacterial phagosome (60). It has been found to downregulate oxidative phosphorylation, mammalian target of rapamycin (mTOR) signaling, and type I interferon response pathways (61).  Sulphonylureas can be used for quick glycemic control. The long acting sulphonylureas like glibenclamide and glimepride have a risk of prolonged hypoglycemia particularly seen in anorexic individuals. Their plasma concentration and their duration of action are modified by drugs acting on cytochrome P450 system and hence monitoring of glycemic status is essential while on these drugs. Thiazolidinediones (pioglitazone) do not produce GI symptoms and are non-hypoglycemic when used as monotherapy. Monitoring of hepatic enzymes is required particularly when TB drugs are co-administered. Alpha-glucosidase inhibitors may be helpful in mild postprandial hyperglycemias. SGLT-2 inhibitors have the risk of further weight loss, euglycemic ketoacidosis, worsening of dehydration in sick patients, and urinary tract infections. They should not be used for glycemic control in patients who are sick and cachexic. In individuals who have no contra-indications they can be continued selectively under close follow-up (62, 63).

 

CO-MORBIDITIES OF DIABETES

 

Cardiovascular Disease in Diabetes and Tuberculosis

 

The commonest cause of mortality in DM is cardiovascular disease due to atherosclerosis manifesting as coronary heart disease (myocardial infarction /cardiac failure), stroke and peripheral vascular disease. TB also has a possible role in chronic vascular inflammation, autoimmunity and inhabitation of TB bacilli atheromatous plaque (64). It also affects the myocardium (65). After successful initiation of TB treatment which is done on a priority basis, DM and cardiovascular status should be assessed. In addition to hyperglycemia management, lifestyle modification, antihypertensive treatment, lipid-lowering therapy, and anti-platelet therapy are the corner stones of management of cardiovascular disease in DM irrespective of the presence or absence of TB. In the presence of hemoptysis anti-platelet drugs are withdrawn or held back. Cessation of smoking and moderation of alcohol has to be counselled about. Anti-hypertensive therapy is initiated during review visits and titrated. Anti-lipid therapy using statins are added gradually and the liver enzymes should be monitored during the course of therapy while on ATT.

 

Renal Dysfunction in Diabetes and Tuberculosis

 

More than a third of individuals with DM develop renal complications due to diabetes. This complicates TB in many ways including increased susceptibility to TB and difficulty in the management of TB (66). In patients with chronic renal failure and on dialysis there is a 6.9‐ to 52.5‐fold risk of developing TB (67). Peritoneal TB is another risk for CKD patients on peritoneal dialysis. The altered immune function in chronic renal impairment increases susceptibility to TB (68). CKD adversely affects TB and its treatment. The anti-TB drugs (ethambutol and pyrazinamide) require dose reduction by up to 50%. Insulin is preferred in most instances for glycemic control. Short acting sulphonylureas or repaglinide can be used as an alternative.

 

Hepatic Dysfunction in Diabetes and Tuberculosis

 

DM liver pathology includes fatty liver disease, NASH, and cirrhosis. In TB, drug induced hepatitis is a concern. In such cases the drugs are withdrawn until resolution of hepatotoxicity. Pyrazinamide is withdrawn completely. Quinolones, ethambutol, and ofloxacin can be used instead of the first line agents. Anti-TB drugs are restarted when the liver enzymes are normalized. Insulin is the drug of choice in severe chronic liver disease with diabetes. Metformin is preferred in fatty liver but withdrawn in cirrhosis.

 

Tuberculosis and Diabetes in HIV – The Triangular Overlap

 

DM and HIV are two independent risk factors for developing TB. The wider prevalence of DM makes DM a more important risk factor for developing TB than retroviral diseases. A significantly higher preponderance of DM over HIV has been reported in cases of pulmonary TB while extra-pulmonary TB was predominant in HIV-TB patients (69). DM is increasing in areas where TB and HIV are rampant. Literature reports on the influence of HIV-co infection on DM with TB have been contradictory. Studies have reported reduced odds of developing DM in HIV infected TB patients (70).  A paradoxical protective effect of HIV on the development of TB was reported (71). However, they were cross-sectional single center studies of limited sample size and had used single random blood glucose tests for screening. But in a case-control study the association between DM and TB in HIV was found to be strong except when HbA1c was used for screening. This may be because of anemia of HIV compromising the true HbA1c value (72). HIV testing is mandatory in all presumptive TB and confirmatory assessment using Gene Xpert MTB/RIF assay for drug resistance.

 

PREVENTIVE METHODS

 

Aggressive DM screening among the population with TB and effective management of both TB and DM can improve outcome on an individual basis. The more effective approach to have an impact at the community level is to have a preventive strategy like vaccination against TB and aggressive prevention and management of DM (29).

 

SUMMARY

 

Epidemiological evidence for an uncharacteristic alliance between non-communicable disease like DM and a communicable disease like TB as a syndemic are overwhelming. A two-to four-fold higher risk of active TB in individuals with DM and twice the prevalence of DM in patients with TB explains the double burden. Ranked among the top ten mortal diseases, the geographical spread of both these diseases is unfortunately overlapping and the co-existence is progressive. They are increasing alarmingly in those regions where health care facilities are limited. DM impacts TB both from infection to disease stage and disease stage to progression stage. Chronic hyperglycemia compromises the alveolar defenses.

 

Latent TB infection is a dormant subclinical disease which lasts for weeks or decades. Immune deficiency either in absolute or relative quantities are sufficient for its re-activation. The clinical and radiological presentations of active TB have been reported to be pulmonary predominantly and atypical when DM co-exists with TB. DM increases the risk of treatment failure, death and relapse. The risk ratio for combined treatment failure and death was 1.69, unadjusted and adjusted risk ratios for death were 1.89 and 4.95 respectively and risk ratio for relapse was 3.89.

 

Bidirectional screening is recommended to improve the outcome in both diseases. Sputum microscopic examination, rapid molecular tests, random plasma glucose and glycosylated hemoglobin are the available among the screening tests with their own merits and limitations.

 

Anti-TB treatment has adverse impact on glycemic control and the complications of diabetes. The metabolism of some DM drugs is modified by ATT which affects glycemic control. Modifications of medications are required in co-morbid illnesses of DM like cardio-vascular diseases, renal, and hepatic dysfunction. Insulin is the drug of choice in lean diabetes, severe hyperglycemia, ketotic states, anorexic patients, and in drug intolerance. Metformin if tolerated has an advantage as a non-hypoglycemic agent with some favorable anti-TB activity.

 

Lifestyle modification, antihypertensive treatment, lipid-lowering therapy, and anti-platelet therapy are the cornerstones in the management of cardiovascular disease in DM and TB. Anti-platelet drugs are withdrawn in patients with hemoptysis. Chronic kidney diseases can predispose to TB and its management is complicated by drug toxicity and dose adjustment of ATT is required along with careful monitoring of response and renal functions. In case of ATT induced hepatotoxicity, ATT is withdrawn and second line agents are substituted. Once liver enzymes normalize the first line drugs are restarted cautiously.

 

Effective preventive strategies like vaccination against TB and aggressive prevention and management of DM will be the approach to be adopted till time throws new light on the means to fight these dual epidemics more effectively.

 

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