Secondary adrenal insufficiency in a young man with HIV and pulmonary tuberculosis, complicated by cerebral toxoplasmosis and seizure

Abstracts

Secondary adrenal insufficiency (SAI) presents with non-specific clinical symptoms, which may overlap with those of HIV and tuberculosis, making diagnosis challenging. We report a case of a 22-year-old Indonesian man, presented with fatigue, intermittent dyspnea, intermittent nocturnal fever, and a significant weight loss of 5 kg over one month. He also reported having unprotected sex with a casual partner. Physically, he presented pale and weak with hypotension . Laboratory examination showed cortisol levels of 28.46 nmol/L and adrenocorticotropic hormone (ACTH) levels of 5.6 µg/dL. Chest x-ray and GeneXpert confirmed pulmonary tuberculosis. Despite an initial negative HIV examination, repeat testing was recommended due to the possibility of a false-negative result. Therefore, the initial diagnosis was SAI due to HIV and tuberculosis. He was treated with hydrocortisone and supportive therapy. Following outpatient discharge, he was re-admitted due to severe headaches, vomiting, and a generalized tonic-clonic seizure. Neuroimaging revealed ring-enhancing lesions, and serology testing was positive for toxoplasmosis IgG and IgM. Repeat testing of HIV was positive with very lowCD4 count. The final diagnosis was cerebral toxoplasmosis, newly diagnosed HIV, and disseminated tuberculosis infection. He responded well to the treatment for 20 days without any complaints and was discharged with anti-retroviral (ARV) and anti-tuberculosis drug (ATD) alongside toxoplasmosis treatment. He remained clinically stable at a 5-months follow-up. Early recognition and treatment of SAI to prevent life-threatening complications, particularly in patients with HIV and tuberculosis co-infection. Thus, early recognition and management are critical to minimize severe complications, particularly cerebral toxoplasmosis.

Highlights

• •Adrenal insufficiency caused by HIV and tuberculosis has non-specific and overlapping clinical symptoms.
• •Early diagnosis of adrenal insufficiency in HIV and tuberculosis plays a crucial role in delaying critical illness.
• •HIV, tuberculosis, and cerebral toxoplasmosis contribute to the HPA dysfunction.

Introduction

Secondary adrenal insufficiency (SAI) is the most common type of adrenal insufficiency (AI) caused by pituitary gland damage, disrupting hypothalamic-pituitary regulation of adrenal cortisol synthesis [1], [2]. The SAI incident was approximately 150–280/million [3]. SAI is associated with human immunodeficiency virus (HIV), approximately 17–19 % [4] and tuberculosis, approximately 6–49.5 % [5]. Despite the higher incidence of SAI in patients with HIV or tuberculosis, diagnosis is usually missed or delayed, which contributes to increasing mortality. Diagnosis of SAI is challenging due to overlapping and non-specific symptoms with HIV or tuberculosis, which are leading causes of the disease. Although SAI is relatively common in patients with HIV or TB, the combined prevalence of SAI due to HIV and tuberculosis has not been sufficiently reported [6].

Cerebral toxoplasmosis is a severe brain infection caused by the Toxoplasma gondii, characterized by cerebral mass lesions with headache, confusion, fever, lethargy, seizures, cranial nerve palsies, psychomotor changes, hemiparesis and/or ataxia [7]. This disease, especially toxoplasmosis encephalitis (TE), is a major opportunistic infection in HIV patients, particularly those with cluster of differentiation (CD4)+ cell counts < 100 cells/mm³, in which its prevalence is relatively higher, approximately 30 %. Co-infection with tuberculosis and TE may occur together, especially in immunocompromised individuals such as those with HIV, who usually present similar symptoms and radiological findings, further complicating diagnosis due to overlapping symptoms [8]. The individual resided in a region with higher HIV and/or tuberculosis incidence, which increases the risk of infection. Additionally, initial clinical signs often indicate a tuberculosis infection [6]. The study reported SAI in a patient with HIV and tuberculosis complicated by cerebral toxoplasmosis and seizure.

Case presentation

A 22-year-old Indonesian man complained of fatigue and intermittent dyspnea. This dyspnea has appeared for two months and is not related to physical activities. He also reported an intermittent nocturnal fever for 3 months. Furthermore, he had a significant weight loss of 5 kg over the past month, which was attributed to poor appetite and inadequate nutritional intake. Additionally, he reported having unprotected sex with a casual partner for approximately 2 years. His medical history had multiple hospitalizations caused by intermittently lower blood pressure near the boundaries of hypotension for 3 weeks. He denied steroid use and had no history of diabetes mellitus, hypertension, asthma, malignancy, or allergic disease.

On admission, he presented pale and weak, with a blood pressure of 92/60 mmHg. Laboratory examination showed hemoglobin of 9.9 mg/dL, C-reactive protein (CRP) of 1.7 mg/dL, basal cortisol levels of 28.46 nmol/L and adrenocorticotropic hormone (ACTH) levels of 5.6 pg/mL. Renal ultrasound revealed no enlargement of adrenal glands (Fig. 1). Chest x-ray suggested pulmonary tuberculosis (Fig. 2), and Mycobacterium tuberculosis (MTB) was confirmed positive with sputum GeneXpert MTB/RIF detected. HIV examination revealed negative results with 3 methods, including an enzyme-linked immunosorbent assay, polymerase chain reaction, and HIV antigen. He has a recommendation for the HIV re-examination again in 3 weeks due to a possible false-negative. He was initially diagnosed with SAI caused by the possibility of HIV and tuberculosis infection. He received a gradual tapering of hydrocortisone of 100 mg thrice daily (day 1–3), 50 mg thrice daily (day 4), 50 mg once daily (day 5), and 25 mg once daily (day 6). He also received norepinephrine of 0.05 mcg/kg/min via syringe pump to maintain blood pressure. Meanwhile, he has administration of other drugs, including ceftriaxone of 1 g twice daily, metoclopramide of 10 mg thrice daily, and paracetamol 500 mg thrice daily (paracetamol was administered as needed for fever). On the 7th day, the hydrocortisone was switched to a methylprednisolone tablet with an equivalent dose of 4 mg once daily due to outpatient preparation and not available of the hydrocortisone tablet in the hospital setting. On the 9th day, he was discharged.

Fig. 1.

Renal ultrasound showed no enlargement of the adrenal glands.

Fig. 2.

Chest x-ray showed reticula’s pattern in parahilar lungs dextra and sinistra.

Although he was absent at the time scheduled for follow-up in the policlinic, he was admitted to the emergency unit 10 days after being discharged with nausea, vomiting, severe headaches, and one episode of generalized tonic-clonic seizures, according to his family’s report. The re-evaluation for HIV examination was positive according to 3 methods, and the CD4 count was three cells/µL (0.49 %). Monitoring of basal cortisol levels was normal (264 nmol/L) due to SAI according to the last hospitalization. Meanwhile, he also detected toxoplasmosis positivity by serology testing, including immunoglobulin G (IgG) and immunoglobulin M (IgM), and brain computer tomography (CT) scan revealed ring-enhancement lesions in several areas of the cerebellum (Fig. 3). Therefore, He was diagnosed with newly-diagnosed HIV, pulmonary tuberculosis, and cerebral toxoplasmosis or encephalitis tuberculosis.

Fig. 3.

Brain CT scan with contrast showed (A) ring enhancement 5.5 × 10.3 cm on the right parietooccipital with perifocal edema, which might be toxoplasma cerebral and (B) several ring enhancements appear in the cerebellum.

He received cefoperazone sulbactam of 1 gr thrice daily, metoclopramide 10 mg thrice daily (when the patient vomits), lansoprazole 30 mg twice daily, and steroids were discontinued. Furthermore, he received additional therapy from pulmonologists who collaborated, including advice on trimethoprim-sulfamethoxazole (TMP-SMX) 960 mg once daily for prophylaxis and beginning initial anti-tuberculosis drug (ATD), especially Isoniazid 300 mg, Rifampicin 450 mg, Pyrazinamide 1000 mg, and Ethambutol 750 mg for 2 months (2HRZE). Meanwhile, a neurologist also contributes to the treatment of seizures, which he received additional therapy of phenytoin loading 750 mg with a maximum speed of 50 mg/min, then maintenance phenytoin 100 mg drip in NaCl 0.9 % 100 mL thrice daily. For toxoplasmosis, he received pyrimethamine loading of 200 mg, then maintenance 25 mg thrice daily, clindamycin 600 mg four times daily, folic acid 1 mg thrice daily, and vitamin B6 1 mg twice daily. After treatment for 20 days, he had no complaints and was discharged as an outpatient with anti-retroviral (ARV) and ATD. ARV in this case included tenofovir 300 mg, lamivudine 300 mg, and efavirenz 600 mg once daily, and was initiated immediately after hospitalization.

One month after the last hospitalization, he showed clinical improvement, and GeneXpert did not detect MTB DNA. Although ARV and ATD were continued, ATD was exchanged from loading to maintaining dose, in which Isoniazid and Rifampicin were continued with doses of 225 mg and 450 mg, respectively, whereas Pyrazinamide and Ethambutol were discontinued. Furthermore, he completed the tuberculosis treatment and is currently stable clinically, 5 months later.

Discussion

SAI usually presents with non-specific clinical symptoms, mimicking other diseases, such as HIV and TB, which causes a delay in establishing the diagnosis and increases mortality [6]. Most patients with AI complained of fatigue, with an estimated percentage of approximately 84–95 %, which is a primary symptom of SAI [2], [9]. The second clinical feature was usually a loss of appetite (53–67 %), followed by weight loss (66–76 %) in AI [2], [10]. Furthermore, fever was reported to appear in AI cases in approximately 60–70 % [2], [11]. Meanwhile, hypotension can also occur in AI patients, particularly during adrenal crisis, which is crucial in diagnosing AI [11], [12]. In this case, the patient was SAI due to several symptoms similar to clinical SAI and had experienced hospitalizations with unclear cause.

The gold standard for diagnosing SAI is ACTH stimulation examination or cosyntropin test, in which the basal cortisol is measured after administration of ACTH 250 μg. Although the ACTH stimulation test was not available at our hospital setting, basal cortisol levels may be tested with a result less than 80 nmol/L (3 μg/dL), showing a strong predictive value of AI [2], [11]. Furthermore, ACTH measurement can be conducted after basal cortisol testing to identify AI types, in which the ACTH level is usually elevated by over 100 pg/mL (22 nmol/L) for primary AI and relatively low or normal for SAI [2]. Meanwhile, the patient also received hormone replacement therapy, especially glucocorticoids, and showed clinical improvement with absent hypotension and with cortisol levels increasing from previously low values to within the normal range, which is leading to suspicion of being a SAI disease [11]. Additionally, hydrocortisone was exchanged with methylprednisolone in a patient with SAI caused by the hydrocortisone tablet that was not available in a hospital setting, and the patient will be under outpatient care. Therefore, the hydrocortisone 20 mg once daily for the patient was equivalent to methylprednisolone 4 mg once daily according to the guidelines of the European Society of Endocrinology and the Endocrine Society [13]. A previous study reported that the recovery of SAI typically occurs after dosage tapering off of glucocorticoids. Although the timing of recovery can be variable, it normally ranged from 6 to 12 months [14]. In this case, a short recovery time was possible due to the infection, with no significant complications, such as the appearance of initial hypotension signs. Additionally, similar case have also been reported in which the quick recovery of SAI due to infectious disease (COVID-19) [15].

HIV and tuberculosis can directly or indirectly damage the adrenal gland, disrupting the hypothalamic-pituitary-adrenal (HPA) axis. In advanced disease, the risk of developing SAI is increased with elevated viral load of HIV, low CD4 count, and disseminated tuberculosis [5], [16]. Confirming the diagnosis of HIV and tuberculosis in this case plays a crucial role in effectively managing the diseases. For individuals with newly diagnosed HIV and tuberculosis, early diagnosis and the prompt initiation of ARV and ATD are recommended as a standard approach. While ARV administration may be delayed when co-infection exacerbation occurs to minimize immune reconstitution syndrome (IRIS), in this report, ARV was initiated after the second hospitalization [17]. Meanwhile, treating tuberculosis using the ATD 2HRZE/4HR approach for new cases showed improvement in clinical outcomes. However, this is also affected by individual adherence to completed treatment for tuberculosis [18].

This case showed cerebral toxoplasmosis, with clinical symptoms appearing especially seizure, neuroimaging showed ring-enhancing lesions, and serology testing was positive for toxoplasmosis IgG and IgM. Although the gold standard for the diagnosis of cerebral toxoplasmosis was biopsy, an alternative to establish a diagnosis can be used, including imaging features, clinical symptoms, and serology testing in low-resource settings [19], [20]. Furthermore, management of cerebral toxoplasmosis usually involves a combination of medications like clindamycin and pyrimethamine, along with folinic acid (leucovorin). In this case, folic acid was used as a substitute in this combination of treatment due to the unavailability of folinic acid at our hospital [21]. Although folic acid can be used, folinic acid is very recommended for managing pyrimethamine toxicity [22].

In conclusion, SAI has non-specific clinical symptoms that are challenging to identify early and can be masked in patients with HIV and tuberculosis. Although the gold standard for diagnosis is ACTH stimulation, basal adrenal levels and ACTH levels can be used as diagnostic tools in a hospital setting with low resources. Meanwhile, its management is ideally hydrocortisone-treated. Despite the lack of available hydrocortisone in the hospital setting, this medication must be switched to other steroids when available, based on equivalent dose. HIV and tuberculosis have contributed to the HPA axis dysfunction. Furthermore, HIV and tuberculosis can also be complications, such as cerebral toxoplasmosis. Therefore, confirming diagnoses of HIV, tuberculosis, and complications such as cerebral toxoplasmosis in this case plays a crucial role in effectively managing the diseases.

CRediT authorship contribution statement

Meilani Yevista Debora Br Pasaribu: Writing – original draft, Visualization, Resources, Project administration, Funding acquisition, Formal analysis, Data curation, Conceptualization. Hermina Novida: Writing – review & editing, Validation, Supervision, Software, Methodology, Investigation.

Statement of patient consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval

Ethical approval is exempt/waived at Dr. Soetomo General Academic Hospital, Surabaya, Indonesia because the report only has one patient.

Funding statement

No funding was received for this manuscript.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.