An unusual case of a dry cough

Shareable abstract

This is the first case report detailing co-infection with both PJP and disseminated histoplasmosis in a patient without HIV infection, and it highlights the immune-suppressive potential of poorly controlled diabetes and liver cirrhosis https://bit.ly/4dXUOX4

A 67-year-old gentleman was visiting Ireland from outside New Delhi, India. He presented to hospital acutely unwell with a 3-day history of pyrexia, confusion, non-productive cough, anorexia and an inability to mobilise independently. Over the preceding 3 weeks he had suffered with gastrointestinal (GI) upset, and noted unintentional weight loss and lethargy over the past 6 months. His past medical history included poorly controlled type two diabetes mellitus (T2DM), he was non-compliant with metformin, and had previous alcohol excess, with no alcohol intake in the past 6 months. He was an ex-smoker with a 20 pack-year history and a retired crop farmer who was fully independent in all activities of daily living before this presentation. Family history was positive for an uncle with Mycobacterium tuberculosis 20 years earlier.

On initial presentation, the patient was hypotensive, tachycardic, tachypnoeic and febrile with a temperature of 38.4°C. His oxygen saturation was 92% on room air. White blood cell count (WCC) was 12×10⁹ per L (normal range: 4.0–11.0×10⁹ per L) and C-reactive protein (CRP) was 37 mg·L⁻¹ (normal range: 0–5 mg·L⁻¹). His serum creatinine was 159 µmol·L⁻¹ (normal range: 59–104 μmol·L⁻¹), urea was 9 mmol·L⁻¹ (normal range: 2.8–8.1 mmol·L⁻¹) and liver function tests (LFTs) were widely deranged. A venous blood gas showed pH 7.3 (normal range: 7.31–7.41), carbon dioxide tension (P_CO2) 4.98 kPa (normal range: 5.5–6.8 kPa), bicarbonate 18.6 mmol·L⁻¹ (normal range: 23–29 mmol·L⁻¹), lactate 2.23 mmol·L⁻¹ (normal range: <1 mmol·L⁻¹), ketones 3.8 mmol·L⁻¹ (normal range: <0.6 mmol·L⁻¹), blood sugar level 3.6 mmol·L⁻¹ (normal range: 3.6–5.3 mmol·L⁻¹). Viral screen and COVID-19 swab were negative.

This patient was visibly cachectic and severely dehydrated with dry mucous membranes and reduced skin turgor. Figure 1 shows a feature noted on general examination.

FIGURE 1.

A feature noted on general examination.

Task 1

Describe the clinical finding shown in figure 1.

Answer 1

Oral hyperpigmentation was noted on examination. This may be a physiological finding but may also represent an underlying pathology such as an infection, syndromic association (e.g. Peutz–Jegher) or endocrine disorder (e.g. Addison's disease).

A full septic screen was performed with blood and urine cultures sent. He was given supplemental oxygen, fluid resuscitated with multiple boluses and commenced on intravenous piperacillin–tazobactam, a broad spectrum antibiotic. It was not possible to send a sputum sample at this time as his cough was non-productive.

Task 2

The patient required repeat fluid boluses to maintain his systolic blood pressure >95 mmHg, mean arterial pressure >65 mmHg and heart rate <100 beats per min. What test do you think is important to perform in the acute setting given the clinical finding seen in task 1?

1. Serum osmolality

2. Serum growth hormone

3. Serum cortisol

4. Thyroid function test

5. Spot urinary metanephrines

Answer 2

Option c, serum cortisol, is correct.

a) Serum osmolality usually comprises the hyponatraemia work-up alongside serum and urinary sodium, urinary osmolality, cortisol and thyroid function tests. The patient is not hyponatraemic.

b) Serum growth hormone is involved in the work-up of endocrine disorders such as acromegaly, which does not fit in with this clinical picture.

c) It is important to check serum cortisol in an acutely unwell patient, particularly if they are hypotensive and tachycardic despite fluid boluses. If there is a suspicion of adrenal insufficiency, patients should be given stress-dose steroids prior to obtaining the serum cortisol level as failure to recognise and treat this quickly can be fatal.

d) It is not unreasonable to check thyroid function tests in this patient if there was a concern about thyrotoxicosis with symptoms such as fast atrial fibrillation, weight loss and GI upset. However, it would be unusual for it to occur so acutely and does not explain his desaturation and shocked state; therefore, a cortisol level is more important to obtain acutely.

e) Urinary metanephrines are the first test in the work-up of pheochromocytoma which would present with tachycardia and hypertensive crisis. This does not fit the clinical picture.

Serum results demonstrated this patient's cortisol level was low at 31 nmol·L⁻¹ (normal range: 166–507 nmol·L⁻¹) and his adrenocorticotropic hormone (ACTH) level was elevated at 112 pg·mL⁻¹ (normal range: 7–63 pg·mL⁻¹). He was immediately commenced on high-dose intravenous hydrocortisone (50 mg four times a day) and responded well to this.

At this point, multiple issues had been identified. First, this patient had a new, acute-onset confusion. Differentials for this included delirium, intracranial pathology, infection or hepatic encephalopathy. Secondly, he was had a new supplemental oxygen requirement with tachycardia and a recent history of a long-haul flight. A pulmonary embolus (PE) had to be considered as well as a potential source of sepsis. Thirdly, he had metabolic acidosis due to raised ketones and lactate, he was hypoglycaemic and hypercalcaemic. Finally, he had low serum cortisol, high serum ACTH and tongue hyperpigmentation and we needed to further investigate for a cause of adrenal insufficiency.

To investigate the cause of acute confusion, computed tomography (CT) and magnetic resonance imaging (MRI) of the brain showed no intracranial abnormality. Serum ammonia was within the normal range (16–60 μmol·L⁻¹). The acute confusion was likely delirium in the context of infection, dehydration and hypercalcaemia. Imaging was obtained to investigate causes of desaturation.

Task 3

Describe the findings of the chest radiograph in figure 2.

FIGURE 2.

Chest radiograph.

FIGURE 2.

Chest radiograph.

Answer 3

Extensive bilateral reticulonodular opacities, most prominent in the lung apices. Differentials included infective and autoimmune causes of granulomatous disease including tuberculosis (TB) and sarcoidosis.

The patient's D-dimer was elevated at 1572 ng·mL⁻¹ (normal range: <500 ng·mL⁻¹). However, CT pulmonary angiography (CTPA) showed no PE and background infective changes. In terms of the metabolic acidosis, an urgent endocrinology consultation was obtained. The low pH was likely being driven by a starvation ketosis for which he was given boluses of dextrose and was commenced on a nasogastric feed with phosphate replacement, to good effect. To investigate the cause of adrenal insufficiency, cross-sectional abdominal imaging was obtained and showed morphological changes of cirrhosis, with portal hypertension (figure 3). There were bilateral adrenal masses, not suggestive of adenoma.

FIGURE 3.

Cross-sectional abdominal imaging.

Liver cirrhosis was in keeping with the pattern of LFT derangement and history of alcohol excess. To further determine these masses, an MRI adrenal was performed which details granulomatous involvement of the glands bilaterally.

Task 4

At this point, considering this man had recently travelled from India and had an ongoing febrile illness, bilateral reticular opacities on chest radiography, and bilateral adrenal enlargement with granulomatous infiltration and hypercalcaemia, what infection would be important to consider and how would one investigate further?

Answer 4

Consider M. tuberculosis infection

• M. tuberculosis should be a consideration in any patient with a cough and febrile illness, especially in a patient who resides in an endemic region. Active TB infection can lead to acute infectious changes on the chest radiograph; in particular, miliary TB can manifest as a vast number of tiny nodules throughout lung fields.

• Hypercalcaemia can occur in active granulomatous disease due to excessive extra-renal 1-α hydroxylase activity as this patient exhibited.

• M. tuberculosis complex can spread to the adrenal glands haematogenously and was once the leading cause for Addison's disease.

To further investigate, sputum should be sent for TB culture and PCR. If the patient is non-productive it would be advisable to proceed to bronchoscopy for bronchoalveolar lavage (BAL) for TB investigation. Interferon-γ release assay can be considered; however, this test identifies the presence of an adaptive immune response directed towards M. tuberculosis antigens and cannot differentiate between active and latent TB infection. Therefore, it is not used in the diagnosis of active infection, although a negative result may help further direct work-up and management. This patient has ongoing confusion and a lumbar puncture could be considered if there are concerns for central nervous system infection, including TB meningitis.

Further investigations included an interferon-γ release assay, sputum for TB culture, acid-fast bacilli and GeneXpert PCR. Bronchoscopy with BAL for culture and lumbar puncture biochemistry and culture were also performed. All the above-listed investigations were negative.

After 1 week, the patient had shown a significant clinical improvement with supportive care and broad-spectrum antibiotics. Unfortunately, due to patient factors an adrenal biopsy was not performed and the patient was very keen to return to India for any further work-up. The patient was reviewed by the Respiratory TB service who advised against empirically treating for TB without having a tissue diagnosis. Treatment selection would also need consideration and close monitoring given the baseline deranged LFTs and background cirrhosis. As he remained well, he was discharged home with strong advice for further TB investigations in India.

Unfortunately, 5 days after being discharged, this man re-presented to the emergency department with acute type one respiratory failure, desaturating to 80% on room air. He was pyrexic to 39.5°C and hypotensive with tachycardia of 170 beats per min. Arterial gases showed oxygen tension of 7.6 kPa and P_CO2 of 5.4 kPa. His WCC was 20×10⁹ per L (normal range: 4.0–11.0×10⁹ per L) and CRP was 284 mg·L⁻¹ (normal range: 0–5 mg·L⁻¹). Serial troponins and brain natriuretic peptide were normal. A portable chest radiograph showed new diffuse bilateral airspace opacification with associate micronodular infiltrate. A further CTPA was requested.

Task 5

Describe the findings shown on CTPA in figure 4.

FIGURE 4.

Computed tomography pulmonary angiography.

FIGURE 4.

Computed tomography pulmonary angiography.

Answer 5

Widespread bilateral ground-glass opacification and consolidation with interlobular septal thickening, small bilateral pleural effusions.

Peripheral blood and urine cultures and urinary antigens were negative. He was trialled on high-flow oxygen; however, despite this, he had increasing oxygen requirements and persistent respiratory distress and was transferred to the intensive care unit (ICU) for intubation and ventilation.

In ICU, β-d-glucan was found to be elevated at 283 pg·mL⁻¹ (normal range: 30–59 pg·mL⁻¹). Bronchoscopy was repeated and BAL samples were once again negative for M. tuberculosis. Samples were also sent for extended fungal culture which was positive for both Pneumocystis pneumonia (PJP) and histoplasmosis. Immunological work-up, autoimmune and viral screens were normal. Although an adrenal biopsy was not performed, considering his bilateral granulomatous adrenal enlargement and histoplasmosis detected on bronchial sampling, we had a high index of clinical suspicion that disseminated histoplasmosis was the aetiology of his adrenal insufficiency.

PJP was treated with co-trimoxazole for 3 weeks as per local guidelines. Histoplasmosis was treated with meropenem, liposomal amphotericin B, ceftazidime–avibactam and linezolid which was later de-escalated to itraconazole that the patient was to continue taking for 1 year. The patient clinically improved and completed inpatient rehabilitation post-ICU stay prior to his discharge. His adrenal insufficiency was managed with maintenance fludrocortisone (100 μg once daily) and hydrocortisone 15 mg/10 mg/10 mg and he remained clinically well.

Discussion

This is a fascinating case which describes two opportunistic infections occurring in a patient from a non-endemic area. Histoplasmosis is a fungal infection caused by the soil-based fungus Histoplasma capsulatum, which is most frequently found in the midwestern USA, North and South America, and Africa, often as a result of bird or bat droppings [1]. Determining prevalence of histoplasmosis can be challenging as infection is mostly asymptomatic or presents as a typical self-limiting pneumonia that is often undiagnosed [1]. It is estimated that although about half a million people get histoplasmosis each year, only 100 000 people develop the disseminated form of disease, as we saw in this case where bilateral adrenal glands showed granulomatous infiltration [2]. The majority of these patients are immunosuppressed, for example, with advanced HIV infection, post-transplant or are using immunomodulator medications, none of which applied to our patient [2]. PJP is an opportunistic infection caused by a commensal respiratory tract fungus Pneumocystis jirovecii, which can frequently occur in immunocompetent patients [3]. A recent study carried found that the incidence of PJP in the UK more than doubled over an 8-year period, a proportion of which, as we saw in this case, were due to disseminated or respiratory fungal infections and not HIV [3]. In fact, it has been reported that PJP occurring in patients without HIV progresses rapidly and may be more severe, which reflects our case where the patient required urgent intubation and ventilation after acutely desaturating to 80% on room air [4]. This highlights the importance of assessing patients for co-infection with P. jirovecii when diagnosed with infections like disseminated histoplasmosis which can be done quite simply by performing BAL and/or sending sputum samples for P. jirovecii PCR and culture.

Opportunistic infections like disseminated histoplasmosis and PJP are often not suspected in immune-competent patients. Apart from a history of T2DM and alcohol-related liver cirrhosis, this patient had no overt immunosuppression such an HIV or malignancy and his immunological and connective tissue disease screens were normal. Historically, diabetes compromises the immune system by, for example, suppressing neutrophils and mononuclear phagocyte systems, causing lymphocyte dysfunction, and by inhibiting the lungs' ability to eliminate pathogens [5]. Interestingly, a retrospective study in India showed that alongside HIV infection, diabetes was one of the most common comorbid conditions associated with disseminated histoplasmosis [6, 7]. There are currently three case reports describing disseminated histoplasmosis in patients with poorly controlled T2DM being their sole immune-compromising factor [8–10]. Similarly, only a handful of case reports detail PJP occurring in patients with T2DM causing immunosuppression [7, 11, 12]. To our knowledge, there are no published case reports detailing co-infection with both PJP and disseminated histoplasmosis in a patient without HIV infection, highlighting the both the rarity of this case and the importance of being aware of the immunosuppressive potential of T2DM and cirrhosis.

Adrenal insufficiency is a life-threatening condition that requires prompt recognition, diagnosis and treatment in all clinical contexts as failure to do so may be fatal. Although autoimmune disease is responsible for 70–90% of cases of acquired adrenal insufficiency, it is important to suspect other causes particularly in an adult patient presenting with new adrenal insufficiency including infectious diseases such as TB or histoplasmosis, metastatic cancer or lymphoma, adrenal haemorrhage or infarction, or drugs [13]. Disseminated histoplasmosis is less common than pulmonary histoplasmosis but when it occurs, it affects the adrenal glands in up to 80% of cases, typically presenting with bilateral adrenal masses [14, 15]. Despite gland infiltration, the hypoadrenalism that our patient developed is rare [14]. Nonetheless, it is important to remember the infectious causes of adrenal insufficiency and screen for them as a cause when clinically indicated, for example, in a septic patient from a high-risk area.

Finally, this case positively reflects access to healthcare resources in Ireland. In regions of the world without adequate diagnostics, people can be treated empirically for the incorrect infection as seen in this case where our clinical index of suspicion for TB was high, curtailing clinical improvement and potentially exposing patients to adverse drug reactions.

Take-home points

This is the first case report detailing co-infection with both PJP and disseminated histoplasmosis in a patient without HIV infection and highlights the immune-suppressive potential of poorly controlled diabetes and liver cirrhosis. Opportunistic co-infections can occur even in seemingly immune-competent individuals and must be identified for clinical improvement.

It is essential to understand the clinical context of adrenal insufficiency and be vigilant about infections like histoplasmosis in at-risk patients. Finally, misdiagnosis of histoplasmosis as TB infection can occur due to the clinical and radiological resemblance of both diseases and should be carefully considered.