Background

IgG4-related disease (IgG4-RD) is a progressive, destructive and sometimes fatal disease. It can present with enlargement of the involved organ that may affect the orbits, lacrimal and salivary glands, pancreas, kidneys, lungs, pleura, peritoneum and other organs, and appropriate clinico-pathological findings sometimes supported with high IgG4 level are needed for diagnosis [1], according to the updated diagnostic criteria published in 2020 [2].

Treatment usually includes oral prednisolone with gradual tapering over a long time while adding a steroid sparing agent like: azathioprine, mycophenolate mofetil and B cell depleting therapy as rituximab [3].

Lung and pleura are not commonly reported in IgG4-RD with the percentage estimated as 15% of cases in some reports [4].

Epidemiology of IgG4-RD in pediatric population is not well studied and the data is usually retrieved from case reports and case series. A recent Turkish single center study identified 8 pediatric cases with IgG4-RD with equal number of both males and females and median age of 13.4 years and pulmonary manifestations in only one case [5].

In this case report, we describe a case of 13-year-old girl presenting with intrathoracic IgG4-RD which is a rare manifestation of a rare disease in a population rarely affected by this disease.

Case presentation

A 13-year-old previously healthy female student presented with gradual exertional dyspnea that improved on leaning forward. The condition progressed over 2 months and was associated with two attacks of coughing blood-tinged sputum, night fever, decreased appetite and weight loss. She was discovered to have a massive pericardial effusion with no clinical or radiographic evidence of tamponade. Therapeutic pericardiocentesis revealed an exudative fibrinous effusion with marked leukocytosis, predominant polymorphonuclear lymphocytes and abundant lympho-plasmacytic cells. Its culture and sensitivity were negative. A Chest Computed Tomography (CT) showed marked pericardial effusion with mild pericardial thickening, left pleural basal thickening in addition to bilateral patchy areas of pulmonary interstitial thickening (consolidation) and ground glass veiling.

An extensive work up showed normal complete blood count (CBC), elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), normal liver function tests apart from hypoalbuminemia, normal kidney function tests, negative tuberculin test, negative blood culture and sensitivity, negative anti-nuclear antibodies, rheumatoid factor and virology, normal complement 3 and 4 and normal thyroid profile, the workup was negative for respiratory viruses and bacteria. She received empirical antibiotics and a short course of steroids and was discharged home.

Despite initial improvement, shortness of breath, hemoptysis, fever and weight loss recurred, and she was readmitted. On examination she appeared toxic, orthopneic, tachypneic, febrile (temp; 38.5 °C-39°C) and tachycardic with no evidence of pulsus paradoxus. Her neck veins were congested and non-pulsating. Her cardiac examination showed increased dullness of the bare area of the heart, distant heart sounds, no murmur or pericardial rub. Bilateral scattered crackles and wheezes were apparent on chest auscultation. The patient had no lower-limb oedema, hepatomegaly or lymphadenopathy.

The investigations including diagnostic pericardiocentesis, and CT-chest (Fig. 1) were similar to the initial admission except for normocytic anemia. In addition three early-morning sputum samples smears with Ziehl–Neelsen (ZN) stain, Interferon-Gamma Releasing Assay (IGRA) test and sputum culture were negative.

Fig. 1
figure 1

CT chest: lung window showed consolidation with air bronchogram in lung midzone and lower lobes. Mediastinal window (lower right) showed massive pericardial effusion, encysted effusion

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The patient received vancomycin and ceftriaxone, with marked improvement. Due to extensive adhesions pericardiotomy was recommended. The encysted pericardial fluid was aspirated. Pericardiotomy was done with multiple biopsies taken from the pericardium. The patient tolerated the procedure without postoperative complications.

Pericardial fluid analysis showed predominant lymphocytes. The Mycobacteria Growth Indicator Tube (MGIT) culture for tuberculosis (TB) was negative after 2-months incubation.

Pericardial Pathology (Figs. 2 and 3) revealed marked storiform fibrosis with excess lymphoplasmacytic infiltrate. The immune-histochemistry showed an increased number of IgG4-positive plasma cells, findings that were compatible with IgG4 related disease. Serum IgG: 2600 mg/dl (700–1600), Serum IgG4: 168 mg/dl (40–120), (value for IgG4-RD > 135 mg/dl), Serum IgG4/total IgG: 0.064 (cut off value for IgG4-RD > 0.08).

Fig. 2
figure 2

Pericardial pathology showed storiform fibrosis with excess lympho-plasmacytic infiltrate

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Fig. 3
figure 3

The immune-histochemistry showed increased number of IgG4-positive plasma cells findings was compatible with IgG4 related disease

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Thus, the patient was diagnosed with IgG4 related disease affecting her pericardium and lungs. She was started on 0.6 mg/kg prednisone together with 2.5 mg/kg azathioprine. After 2-weeks the patient returned to her usual physical activity. After three months, there was no recurrence of pericardial or pleural effusion, with normalization of hemoglobin, ESR and CRP. However, the lung lesions persisted and she was switched to mycophenolate mofetil (MMF) and rituximab was discussed.

2 years later, the patient started to complain of progressive dyspnea, with high ESR, CRP, so the decision was to start rituximab. The patient received 4 intravenous doses of rituximab 500 mg, each dose was one week apart from its following dose. After those four doses, the patient showed marked initial improvement of her general condition, dyspnea and cough.

6 months later, the patient started to redevelop progressive dyspnea, and productive cough with whitish sputum, culture and sensitivity were negative, the patient was not feverish, the chest auscultation showed left basal inspiratory crepitations. The hemoglobin level was 9.4 mg/dL, normal white blood cell count and differential, normal basic metabolic profile, ESR = 16, CRP was negative.

CT chest with intravenous contrast (Fig. 4) was done and showed: diffuse mediastinal infiltrative soft tissue mass lesion is seen surrounding the mediastinal structures with no evidence of obstruction, associated with bilateral circumferential pleural and fissural thickening, more evident on the left side, with bilateral pleural effusion, there was also pericardial thickening with effusion. There was bilateral diffuse thickening of central and peripheral pulmonary interstitium in the form of hilar and peribronchovascular soft tissue thickening and thickening of interlobular septae.

Fig. 4
figure 4

CT chest showing diffuse mediastinal infiltrative soft tissue lesion, pericardial thickening with effusion, bilateral diffuse thickening of central and peripheral pulmonary interstitium

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Echocardiography showed normal ejection fraction, EPAP = 30 mmHg, no pericardial involvement.

Left thoracotomy was done, superior mediastinal and pleural biopsies were taken, the pathology showed: inflammatory fibrosing reaction with no active IgG-4 related disease in the tissue examined.

The patient received one dose of intravenous rituximab 500 mg and oral prednisolone was increased to 1 mg/kg/day and the patient was discharged for follow-up.

One week later the patient developed a sudden onset of massive hemoptysis. She was brought to emergency room with altered mental status, bradycardia, hypotension and hypoxia. She was intubated, and mechanically ventilated but despite resuscitation the patient passed away. The timeline of the events is shown in Fig. 5 (Fig. 5: timeline of the events).

Fig. 5
figure 5

Timeline of the events. (Yr: years, Dx: diagnosis, IgG4-RD: Immunoglobulin G 4 related disease, AZA: azathioprine, MMF: mycophenolate mofetil, RTX: rituximab)

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Discussion and conclusions

This is a case report of a rare presentation of intrathoracic IgG4-RD in a young 13-year-old female. She fulfilled definitive diagnosis according to the revised comprehensive diagnostic (RCD) criteria for IgG4-RD having all three criteria: 1) organ involvement; 2) serum IgG4 concentration > 135 mg/dl; 3) positive for pathological sub-items. Constitutional symptoms and inflammatory markers were evident from the start paralleling the activity of the disease and improved later on with treatment.

We have searched Pubmed using: (IgG4-RD AND pediatric) starting from all the time till the date of July17th, 2022 and this search resulted in identifying 28 cases of IgG4-RD in pediatric age group, along with 23 cases extracted from another review [6] and extra 8 cases from single center experience [5], a total of 59 cases as shown in (Table 1: literature review of pediatric IgG4-RD).

Table 1 literature review of pediatric IgG4-RD
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As most of cases, a course of prednisolone and azathioprine was used as a starting regimen in our case and upon relapse rituximab was started. Along with medical treatment, pericardiotomy is a possible relieving procedure that proved to be effective in IgG4-RD with pericardial involvement.

Unfortunately, our case developed a fatal relapse unlike most of the reported cases which succeeded long remission, bearing in mind that a considerable number of the reported cases have no documented follow up.

In our case, the second biopsy, taken from the mediastinum and pleura, showed no IgG-4 positive plasma cells, probably resembling an end to the activity process by a permanent damaging fibrosis. We presume that this fibrosis eroded the bronchial blood vessels and caused such fatal hemoptysis. This presumption is supported by two facts; first of which is the normal ESR and CRP of the patient at that time, and the second is the poor response to rituximab in its second cycle.

In a literature review of 25 pediatric cases of IgG4-RD, the median age of the cases was 13 years, with 64% were girls. The predominant manifestations were IgG4-related orbital disease (44%) and autoimmune pancreatitis type 1/IgG4-related pancreatitis (12%) with pulmonary manifestations occurring in only 2 cases. Our case conforms to the average age and main gender of such cases but with a rare presentation; intrathoracic one. 24 extra cases were added to our table from this review [6].

In a recent single center experience, the researchers reviewed a total of eight patients, the details of those cases are included in the table, with a median age of 13.4 years. The manifestations were IgG4-related ophthalmic disease (six patients), IgG4-related lymphadenopathy (one patient), and IgG4-related sialadenitis and lymphadenopathy, pancreatitis, ulcerative colitis, and pulmonary manifestations (one patient). Relapse occurred in only two patients. This highlights the rarity of pulmonary involvement in pediatric age group and highlights the fact that relapse does not occur in the majority of cases [5].

As many of the searched cases (Table 1), our case was associated with systemic constitutional symptoms along with elevated inflammatory markers like ESR and CRP, so both, the constitutional manifestations and the inflammatory markers may provide non-invasive ways to monitor the disease activity and enlighten the management decisions.

In spite of discussing only orbital involvement, a review studying clinicopathological characters of orbital IgG4-RD showed absence of pathognomonic findings associated with adult version of the disease, like storiform fibrosis and obliterative phlebitis [7]. Serum IgG4 was elevated in 2 out of 4 cases. The four studied cases had treatment-responsive clinical course. This was contrary to our case which had pathognomonic histopathological features, elevated serum IgG4 and a frequently relapsing clinical course. Interestingly, the four reviewed cases had positive ANA with high titers in comparison to negative ANA in our case.

As regarding adult IgG4-RD cases with pericardial involvement, in one recent review of IgG4-RD with pericardial involvement, 32 published cases were included [8]. The mean age was 64 years and 65.7% of patients were males. IgG4-related pericarditis was mostly associated with pleural involvement, as in our case. In most cases, a pericardial biopsy was done to support the diagnosis of IgG4-RD and serum-IgG4 levels were ≥ 135 mg/dL in 86% of cases. Those findings are the same as in our case too. Most patients were initially treated with glucocorticoids, pericardiectomy or a combination of both. Only one patient was treated with rituximab as monotherapy.

To conclude: we report a case of 13-year-old female presented with a pediatric intrathoracic IgG4-RD, which is a rare form of IgG4-RD. Our case suffered from frequent relapses and ended in fatal hemoptysis, the exact cause of which has not been established. Being a disease that may affect pediatric age group, and may involve the lung, pleura and pericardium, not only the rheumatologist should be aware of this rare disease, but also the general pediatrician, the cardiologist and the pulmonologist. To our knowledge, this is the first case report to describe a case of pediatric IgG4-RD who developed fatal hemoptysis as a result of pulmonary affection.