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| RADIOLOGY ROUNDS |
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| Year : 2023 | Volume
: 3
| Issue : 1 | Page : 61-64 |
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An infant with non-resolving pneumonia: A clinico-radiological approach to diagnosis
Chirag Thakur1, Anmol Bhatia2, Uma Nahar3, Hitaishi Mehta4, Pankaj C Vaidya1, Avnesh Reddy1, Joseph L Mathew5
1 Department of Pediatrics, PGIMER, Chandigarh, India
2 Department of Radiodiagnosis and Imaging, PGIMER, Chandigarh, India
3 Department of Histopathology, PGIMER, Chandigarh, India
4 Department of Dermatology, PGIMER, Chandigarh, India
5 Department of Pediatrics, Division of Pediatric Pulmonology, PGIMER, Chandigarh, India
| Date of Submission | 20-Jan-2023 |
| Date of Decision | 24-Jan-2023 |
| Date of Acceptance | 25-Jan-2023 |
| Date of Web Publication | 27-Feb-2023 |
Correspondence Address:
Prof. Joseph L Mathew
Department of Pediatrics, Division of Pediatric Pulmonology, PGIMER, Chandigarh
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ipcares.ipcares_20_23
How to cite this article:
Thakur C, Bhatia A, Nahar U, Mehta H, Vaidya PC, Reddy A, Mathew JL. An infant with non-resolving pneumonia: A clinico-radiological approach to diagnosis. Indian Pediatr Case Rep 2023;3:61-4 |
How to cite this URL:
Thakur C, Bhatia A, Nahar U, Mehta H, Vaidya PC, Reddy A, Mathew JL. An infant with non-resolving pneumonia: A clinico-radiological approach to diagnosis. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Mar 22];3:61-4. Available from: http://www.ipcares.org/text.asp?2023/3/1/61/370530 |
This case describes an infant boy who presented with clinical and radiological features of pneumonia. He was managed at two private hospitals with oxygen and multiple intravenous (IV) antibiotics, but did not improve, hence was referred to our institution. A careful identification of the available chest radiographs showed cystic lucencies in the lungs, raising the possibility of Langerhans cell histiocytosis (LCH). However, none of the usual clinical features of LCH were present. Bone marrow examination and bronchoscopic lavage analysis did not find any evidence of LCH. He developed skin lesions while in hospital, and a punch biopsy identified the classical histopathological features of LCH. This case highlights the challenges in managing children presumed to have pneumonia and the step-wise approach to diagnosis and management of the clinical phenotype of nonresolving pneumonia.
| Clinical Description | |  |
A 13-month-old boy presented with a fever for a month, cough for 20 days, and fast breathing for 15 days. The fever was of moderate grade, never exceeding 101°F, tended to rise in the evening, and was partially relieved with antipyretics. Ten days after the onset of fever, he developed dry, nonparoxysmal cough that was not associated with wheezing. This was followed by fast breathing associated with chest in-drawing. His feed intake also diminished. He was hospitalized for 7 days elsewhere, diagnosed with pneumonia, and treated with oxygen and IV antibiotics (details unknown). The chest X-ray showed diffuse reticulonodular infiltrates [Figure 1]a. He failed to improve and was referred to another hospital, where a diagnosis of nonresolving pneumonia was considered. He received IV vancomycin and meropenem, along with oral azithromycin and linezolid. He underwent a noncontrast computed tomography (CT) thorax scan [Figure 2] that was reported as infectious bronchiolitis or pneumonitis. After a hospital stay of 6 days, the infant was referred to our institution for persisting fever, respiratory distress, and requirement of oxygen. | Figure 1: (a) The chest X-ray showing diffuse reticulonodular shadows in both the lungs. (b) The chest X-ray showing diffuse reticulonodular shadows with interspersed areas of cystic lucencies (arrows). (c) The chest X-ray showing improvement following therapy
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 | Figure 2: Axial CT sections (lung window) showing small cysts with interspersed areas of interstitial thickening and ground-glass opacities (arrows). CT: Computed tomography
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We reviewed the history to identify the pattern and course of the symptoms. There was no history of any antecedent viral illness before the onset of symptoms. Over the preceding 4 weeks, fever, cough, respiratory distress, and diminished feeding had not improved. We then looked for any history suggesting other systemic involvement. There was no history of ear discharge or head banging; rash or any skin lesion; interrupted feeding with suck-rest-suck cycles associated with sweating on the forehead, or episodes of turning blue; vomiting, abdominal distension, or diarrhea; or irritability, lethargy, seizures or altered sleep-wake cycle; progressive pallor, or bleeding from any site. There was no discernible weight loss.
The past history revealed that when the infant was 6 weeks old, he had developed a red, painful swelling behind the ear that had been incised and drained of pus. The postauricular abscess had resolved within a week with oral and topical medications. There was no history of tuberculosis or similar illness in any family member. The infant was born at full term of nonconsanguineous parents; he was delivered by cesarean section for breech presentation. The birth weight was 2.7 kg. He received vaccinations as per the National Immunization Schedule. Developmentally, he had delayed attainment of language milestones (only babbling by 1 year). The milestones in the other domains were normal. According to the parents, the hearing was normal.
At admission, the infant was febrile (101°F), heart rate was 164/min, respiratory rate was 64/min with subcostal and intercostal retractions, blood pressure was 88/56 mm Hg, capillary refill time was 2 s, and SpO2 was 53% in room air (increasing to 95% with oxygen). The weight was 7.6 kg (−2.54 z-score), length was 77 cm (−0.36 z-score), weight-for-length (−3.31 z-score), head circumference was 45.5 cm (−0.81 z-score), and mid-upper arm circumference was 11.5 cm. There was a mild pallor and central cyanosis but no clubbing, lymphadenopathy, elevated jugular venous pressure, edema, or rash. The infant had sparse, easily pluckable scalp hair, and a pectus carinatum. A Bacille Calmette Guerin (BCG) scar was present. Ear, nose, and throat examinations were normal. There was no tenderness over the bones.
The respiratory system examination revealed a centrally positioned trachea, symmetric chest shape and movements, and apex beat located 1 cm medial to the midclavicular line in the left fourth intercostal space. The percussion note was normal. Fine crackles were audible all over the chest. Per abdominal examination was normal. The liver was palpable 3 cm below the right costal margin (span 9 cm); it was soft, regular, nontender, nonnodular, and had leafy margins. The spleen was palpable 2 cm below the left costal margin and was soft. There was no sign of free fluid on percussion. The cardiovascular and central nervous system examinations were unremarkable.
What are the differential diagnoses based on the clinical phenotype at this stage?
The infant presented with a clinical picture of pneumonia and Type I respiratory failure, unresponsive to antibiotic therapy. Knitting the history and examination findings, disseminated tuberculosis (affecting the lungs, liver, and spleen) was considered the first differential. The salient history of an unusual infection in early infancy (postauricular abscess) raised the possibility of a primary or secondary immune deficiency; the most likely being chronic granulomatous disease (CGD) or HIV infection. Additional differential diagnoses considered were storage disorders (Niemann-Pick type C and nonneuronopathic Gaucher's disease) on account of pulmonary involvement and hepatosplenomegaly. Infiltrative disease (i.e., leukemia) was also considered in view of pallor and hepatosplenomegaly, although the predominant respiratory symptoms went against it. A remote possibility of childhood interstitial lung disease with secondary infection was also thought of, on account of the unusual course and need for oxygen. We proceeded to review the radiological images from the previous hospitalizations.
What are the salient features in the chest X-rays?
The first chest X-ray done on the 14th day of illness showed bilateral hyperinflated lungs with diffuse reticulonodular shadows, suggesting diffuse lung disease [Figure 1]a. The second X-ray done on the 30th day of illness (at presentation to us) also showed diffuse reticulonodular shadows bilaterally, but the intervening cystic lucencies that were visible suggested a cystic lung disease. The soft tissues and bones appeared unremarkable [Figure 1]b. LCH was also considered based on the presence of pulmonary cystic lucencies.
Noncontrast CT scan done during the second hospitalization showed diffuse ground-glass opacity and interstitial thickening, with small cystic lesions diffusely scattered in both the lungs. Thus, the radiological differential diagnoses were interstitial lung disease and LCH.
What is the next step in workup?
We proceeded to investigate for LCH. The skeletal survey, including the long bones and skull, did not show any lytic lesion. Bone marrow examination was normocellular, and there were no atypical cells. Immunohistochemistry for CD1a and S-100 (LCH markers) did not reveal any infiltration of cells with LCH phenotype. Therefore, LCH was ruled out.
The infant was also investigated based on the clinical differential diagnoses considered. Gastric lavage samples sent thrice did not reveal acid-fast bacilli on smear, and the GeneXpert was negative. Ultrasonography of the abdomen was also normal, except for hepatosplenomegaly. Screening chest X-rays of the family members did not show evidence of tuberculosis. Screening tests for HIV and CGD (nitroblue tetrazolium test and dihydrorhodamine assay) were negative.
Considering isolated pulmonary histiocytosis, due to the presence of cystic lucencies and the absence of systemic features, flexible bronchoscopy was done, and bronchoalveolar lavage (BAL) was obtained. The bronchoscopic examination was normal. The BAL cytology revealed occasional histiocytes with nuclear grooves; however, histiocytosis markers CD1a and CD207 (langerin), were negative. Investigations to identify microorganisms did not show evidence of bacterial, tubercular, or fungal infection. However, BAL showed DNA of cytomegalovirus (CMV) detected by polymerase chain reaction.
What should be done now to establish the diagnosis?
At this stage, since none of the clinico-radiological differential diagnoses considered, could be confirmed with certainty, we decided to perform an open lung biopsy, followed (if required) by a liver biopsy. However, before this could be done, the infant developed pruritic, papulonodular skin lesions with whitish scales on the surface [Figure 3]. These were localized to the abdomen, in the epigastric and umbilical areas, appeared in crops, and had a centripetal distribution. | Figure 3: Papulonodular skin lesion with scaling. A punch biopsy was obtained from the encircled lesion
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Consultation with a dermatologist was sought, who opined that it was consistent with LCH. A punch biopsy was obtained for histopathological examination, which revealed acanthotic epidermis with collection of cells in the papillary and upper dermis layers, comprising histiocytes, lymphocytes, and occasional eosinophils infiltrating the overlying epidermis. A few histiocytes showed convoluted nuclei with nuclear grooving. The immunohistochemical staining of these cells showed diffuse positivity for CD1a and CD207, confirming LCH.
Now that the diagnosis of LCH was established through the fortuitous appearance of skin lesions on the 38th day of illness, investigations were planned to rule out the systemic involvement. As LCH is associated with diabetes insipidus, urine and serum osmolarity were examined but were normal. Therefore, intracranial imaging was not planned. The final diagnosis was multisystem (lung, liver, spleen, and skin) LCH (although histopathologic evidence was available only from the skin). The CMV in BAL was considered an incidental coinfection.
Management, Course, and Outcome
The infant received chemotherapy with vinblastine (6 mg/m2 weekly for 6 weeks) and oral prednisolone (40 mg/m2 for 4 weeks, followed by tapering) for the LCH. He also received therapy for CMV (IV ganciclovir 5 mg/kg/day was planned for 6 weeks, followed by oral valganciclovir 15 mg/kg/dose twice daily for 6 months). The respiratory distress subsided over 8 days, and oxygen could be omitted after 10 days of initiating both treatment protocols. At discharge after 16 days of hospital stay, he maintained SpO2 of 97%–98% in room air. A chest X-ray done after 2 weeks of therapy also showed improvement in terms of clearing of reticulonodular shadows [Figure 1]c.
| Discussion | | |
LCH is a relatively uncommon condition in children. The incidence among children <15 years of age is reported as 4–9 cases per million per year.[1] LCH has a wide clinical spectrum ranging from benign localized disease to disseminated multisystem life-threatening disease. The organs most commonly affected include the skin, bone, lymph nodes, lungs, liver, spleen, bone marrow, pituitary gland, and central nervous system.[2] The pathophysiology of LCH is poorly understood. It has characteristics of both a reactive as well as a neoplastic process. Recently, mutations of genes in the MAP kinase pathway and BRAF gene have been demonstrated as the cause of abnormal proliferation of Langerhans cells.[3]
The clinical features of LCH are diverse and depend on the organs involved; however, fever is often present.[4] Cutaneous lesions include seborrheic scaly lesions, papules, nodules, and even masses.[5] Hematopoietic, spleen, and liver involvement are considered risks for poor prognosis. Lung involvement is generally a part of multisystem disease, although isolated pulmonary histiocytosis has been reported. The definitive diagnosis of LCH depends on the histopathologic demonstration of LCH cells and positive immunohistochemistry for CD1a and/or CD207, in specimens obtained from the involved site.[1]
Radiologic imaging can aid the diagnosis and help identify a site for biopsy. However, chest X-rays have limited sensitivity and specificity. A high-resolution CT is sensitive for the demonstration of characteristic findings, including nodular or reticulonodular shadows, followed by diffuse cystic lesions. The pulmonary nodules are typically centrilobular, peribronchial, or peribronchiolar in distribution.[6] Although the classical features of LCH were not evident in the noncontrast CT of this infant, it was decided to avoid additional radiation exposure by repeating a contrast-enhanced CT.
In the index case, BAL fluid revealed CMV. CMV is an unusual organism in the lungs of immunocompetent individuals. However, there are a few reports of CMV in LCH, and some authors consider that it could be a cause for clinical syndromes associated with hemophagocytosis, such as hemophagocytic lymphohistiocytosis and LCH.[7],[8]
In conclusion, this case highlighted the challenges in confirming the clinico-radiological diagnosis and the step-wise approach in such situations.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Sterlich K, Minkov M. Childhood langerhans cell histiocytosis: Epidemiology, clinical presentations, prognostic factors, and therapeutic approaches. In: Rare Diseases – Diagnostic and Therapeutic Odyssey. 2021. Available from: http://dx.doi.org/10.5772/intechopen0.96543. [Last accessed on 2022 Dec 20].  |
| 2. | Barclay M, Devaney R, Bhatt JM. Paediatric pulmonary langerhans cell histiocytosis. Breathe (Sheff) 2020;16:200003. |
| 3. | Chakraborty R, Hampton OA, Shen X, et al. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 2014;124:3007-15. |
| 4. | Uppal P, Bothra M, Seth R, et al. Clinical profile of langerhans cell histiocytosis at a tertiary centre: A prospective study. Indian J Pediatr 2012;79:1463-7. |
| 5. | Poompuen S, Chaiyarit J, Techasatian L. Diverse cutaneous manifestation of Langerhans cell histiocytosis: A 10-year retrospective cohort study. Eur J Pediatr 2019;178:771-6. |
| 6. | Bano S, Chaudhary V, Narula MK, et al. Pulmonary langerhans cell histiocytosis in children: A spectrum of radiologic findings. Eur J Radiol 2014;83:47-56. |
| 7. | Rigaud S, Fondanèche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 2006;444:110-4. |
| 8. | Kawakubo Y, Kishimoto H, Sato Y, et al. Human cytomegalovirus infection in foci of langerhans cell histiocytosis. Virchows Arch 1999;434:109-15. |
[Figure 1], [Figure 2], [Figure 3]
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