CASE PRESENTATION :

A 50-year-old male farmer presented one day to our outpatient department with dramatic complaints of severe respiratory distress that was present only in sitting and standing posture along with walking and slumped into the floor of our outpatient department and we rushed to check his SPO2 with a pulse oximeter that showed marked hypoxia which gradually recovered while he kept lying on the floor.

We further noticed that in the sitting posture, patient?s saturation started to fall after 2-3 min and reached 87% after 5 min of sitting and he could not sit beyond that period. Patient was unable to tolerate standing posture for more than few minutes. SpO2 reached 78% after 3 min of standing and patient could not stand anymore because of severe dyspnoea. His general physical examination findings on admission revealed: consciousness, clear; digital clubbing, cyanosis, peripheral oedema, pallor, icterus, jugular venous distension, mucocutanous telangioectases and spider nevi were absent; body temperature 35.7?; blood pressure 130/80 mmHg in supine position and there was no significant postural drop in blood pressure; pulse rate, 90 beats/ min, regular; resting SpO2, in lying down position was 95% (indoor atmospheric pressure) and respiratory rate of 42/min; Breathing was shallow with no accessory muscle retractions. One observer RB noted presence of bilaterally symmetrical restriction of movements in the wrist joints and interpreted it as active synovitis due to rheumatoid arthritis and asked for bilateral X ray hands AP view. Apart from wrist joint involvement, all other joint examinations were within normal limits.

This fall in oxygen saturation was associated with simultaneous increase in respiratory rate. Oxygen saturation, tachycardia and tachypnea did not improve with administration of supplementary oxygen in supine, sitting as well standing positions. Ambulation did not lead to further drops in blood saturation.

No kyphoscoliosis but fine late inspiratory crackles were heard on the dorsal side of the lower lung region of both lung on chest auscultation; and no cardiac murmur/thrill/gallop or rub was heard. His ENT examination was absolutely normal ruling out any possibility of laryngeal malignancy.

Patient was almost all right 6 months back with no significant past medical history including no childhood illness, no history of respiratory, liver or cardiac disease. Illness started with occasional dry cough and breathlessness on exertion that increased with time. Since last 1 month he developed fever, cough with expectoration, decreased appetite and arthralgia/myalgia for that he received ATT but with no improvement. Arthralgia was associated with slight morning stiffness. He was an occasional smoker but regular tobacco chewer.

INVESTIGATIONS:

The findings of biochemical study and blood count showed no significant alterations (summarized in Table 1).

Table?1.?Laboratory Data on Admission

On chest X-ray few bilateral diffuse interstitial infiltrates in all lung fields were noted alongwith some reticulonodular shadows in both mid and lower zone over both lung fields (Fig 1). X-Ray hands showed partial loss of joint space between carpal bones of distal row (Fig 2).

USG abdomen was normal with no evidence of organomegaly and normal liver parenchyma.

Electrocardiogram demonstrated sinus rhythm with a normal axis.

Resting arterial blood gas analysis (on supine position under room air) revealed mild hypoxemia with respiratory alkalosis: pH- 7.427; PaCO₂- 33.1 mmHg; PaO₂-57.4 mmHg; SaO₂-90.0%; and A-aO₂, 51.2 mmHg (increased); showing mild oxygenation failure. Patient did not allow for ABG in standing and post walk (exercise) because of respiratory distress.

On  pulmonary function testing: Spirometry showed restrictive pattern with increased FEV1/FVC ratio of 100% with decreased FEV1-1.85 L; 70% and FVC-2.35 L; 67% .

Computerised Tomography of thorax showed patchy, mainly peripheral areas, predominantly subpleural, and bibasilar reticular opacities. Minimal ground- glass opacities found in bilateral lung parenchyma. Subpleural fibrosis with traction bronchiectasis noted in bilateral upper lobe, right middle lobe with more marked changes in bilateral lower lobes. Bilateral interstitial septal thickening along-with right oblique fissure, Multiple peripherally arranged (sub-pleural) honeycombing were also noted. Radiologist reported these HRCT patterns as ?con?dent? or ?certain? radiographic diagnosis of IPF without knowledge of history of the patient. The pulmonary vasculature was also normal, with no evidence of pulmonary emboli or arteriovenous malformations (AVMs). (Fig 3).

A transthoracic echocardiogram was performed with the patient in both the supine and upright positions.Mildly enlarged right atrium and right ventricle was noted. TR Jet velocity gradient was 18mmHg and 32 mmHg in supine and standing positions respectively. Intravenously administered agitated normal saline (Bubble Contrast Echocardiography) was not detected in the left atrium even after six cardiac circles excluding the presence of intra-cardiac or intrapulmonary shunts in both supine and standing position (Fig 4). No evidence of pericardial effusion, constrictive pericarditis found on Echo.

 Pulmonary angiogram was not performed due to the respiratory distress.

Right heart catheterization facility was not available at our center to assess right atrial pressures/PAH.

DIFFERENTIAL DIAGNOSIS

Interstitial Lung Disease

Cause: 1. Secondary to Rheumatoid Arthritis

             2. Idiopathic Pulmonary Fibrosis

TREATMENT :

The patient was started on prednisone at a dose of 0.5 mg/kg lean body weight (LBW) per day orally along-with azathioprine 50mg per day orally, that was increased to 75mg after 7 days and to 100mg per day
after another 7 days.

OUTCOME AND FOLLOW-UP : 

Patient responded slightly after 7 days of therapy, amount of fall in SaO2 in sitting posture decreased but no major improvement in platynea. With 14 days of combination therapy patient was tolerating standing posture better than previously. Therapy was continued and asked to follow up after 2 weeks but patient did not came rather he came after 3 weeks with hypovolemic shock (acute Gastroenteritis following food poisoning) and respiratory failure and succumbed to death in-spite of all resuscitative measure and ventilator support. Attendants of patient told that patient was doing well with prednisolone-azathioprine before this episode of Acute GE.

DISCUSSION :

Only few cases of this syndrome associated with various etiologies have been reported in literature. However, to the best of our knowledge, the association of this syndrome with Interstitial Lung Disease and specifically with IPF has not been reported yet.

Three primary mechanisms have been postulated for this rare clinical phenomenon: intra-cardiac shunting, anatomic pulmonary vascular shunting, and ventilation-perfusion mismatching/pulmonary parenchymal shunts ^{(2,5, 8)}  with inter-atrial communications being the most common etiologic association.^{(6, 9, 10)}

Platypnea and orthodeoxia have been described in several cardiopulmonary disorders categorised as ⁽¹¹⁾-

1. Cardiovascular? Intracardiac shunts,⁽¹²⁾ patent foramen ovale, ^(5,13)   atrialseptal defect and atrial septal aneurysm,^(14-16)   bioprosthetic tricuspid valve stenosis,⁽¹⁷⁾ transposition of the great arteries, ⁽¹⁸⁾ eosinophilic endomyocardial disease, ⁽¹⁹⁾ constrictive pericarditis, ^(20-21)  atrial myxoma, ⁽²²⁾    aortic aneurysm, ^(23-24)  aortic elongation, ⁽²⁵⁾ pericardial disease, right ventricular remodelling, a prominent Eustachian valve, aortic dilation, ⁽²⁶⁾ pericardial effusion. ⁽²⁷⁾

2. Pulmonary- Postpneumonectomy, ⁽²⁸⁾ amiodarone-induced pulmonary toxicity, ⁽²⁹⁾ recurrent pulmonary emboli, ⁽⁵⁾ adult respiratory distress syndrome, ⁽³⁰⁾ Pulmonary AVM, ⁽³¹⁾   pulmonary hypertension in obstructive sleep apnea syndrome, ⁽³²⁾  true vascular lung shunts, ⁽²⁾ bronchogenic carcinoma, ⁽³³⁾   interstitial fibrosis, ⁽³⁴⁾  pulmonary embolism, ⁽³⁵⁾ chronic obstructive pulmonary disease (COPD), ^(36-37)  emphysema, pneumonectomy ^(16,38-39)  cryptogenic fibrosing alveolitis. ⁽⁴⁰⁾

3. Hepatic- Laennec's cirrhosis/hepatopulmonary syndrome, porto- pulmonary hypertension. ⁽⁴¹⁾

4. Infectious- Hydatid cyst, ⁽⁴²⁾ cytomegovirus and pneumocystis jiroveci infection. ⁽⁴³⁾

5. Neurological- Parkinson?s disease, ⁽³⁶⁾ diabetic autonomic neuropathy. ^{(44 )}

6. Miscellaneous- Laryngeal carcinoma, ⁽⁴⁵⁾ unilateral paralysis of the diaphragm, ⁽⁴⁶⁾  blunt chest wall trauma, ⁽⁴⁷⁾ new onset ileus, ⁽⁴⁸⁾ radiation-induced bronchial stenosis, ⁽⁴⁹⁾  broncho- pleural ?stula, ⁽⁵⁰⁾  fat embolism, ⁽⁵¹⁾  propafenone overdose in Ebstein anomaly, ⁽⁵²⁾  osteoporosis and severe kyphosis, ⁽⁵³⁾  Diabetic Autonomic Neuropathy, ⁽⁵⁴⁾  progressive autonomic failure, ⁽⁵⁵⁾   acute organophosphorus poisoning. ⁽⁵⁶⁾ 

      Further investigation should be focused on the detection of probable intra-cardiac or intrapulmonary shunts using Contrast Echocardiography with intravenous injection of microbubbles (agitated saline), a widely accepted and non-invasive method for this purpose. It is also used to screen the patient of hypoxia due to acquired lung disease to assess the presence and location of anatomic right-to-left shunts.^(57,58,59)  The appearance of the contrast into the left chambers is evidence for intracardiac shunt, if early (within three heartbeats), and extracardiac shunt, if delayed(after  six cardiac cycles). ^{(5, 59-61)}   Moreover, this technique can image intrathoracic malformations. ⁽⁶¹⁾ Although even pulmonary angiographic techniques are incapable of detecting multiple small arterio-venous communications.⁽⁶²⁾

Orthodeoxia noted in pulmonary condition has different mechanism than intra cardiac shunting and also varies with various aetiologies. It has been stated that, with the patient in upright posture, increased flow across the AVM (pulmonary shunting) as in severe chronic obstructive pulmonary disease, and in hepatic cirrhosis also; occurs due to gravitational effects, thereby increasing the shunt.^(1,37,63)

Altman & Robin ⁽¹⁾ and Glazier JB et al ⁽⁶⁵⁾ described the existence of preferential increased basilar blood ?ow compared with the apical regions secondary to effects of gravity (enlargement of zone I) in cases of predominately basilar lung disease. Comparatively, alveolar pressure remains constant. When the ventilatory mechanics become impaired, alveolar pressures can become substantially elevated. This phenomenon is apparent in apical segments and is exacerbated on assumption of upright postures (diffuse Zone I phenomenon). Ultimately, this can result in a decrease in pulmonary artery pressures and pulmonary capillary compression resulting in respiratory dead space through a decrease in blood ?ow (ventilation-perfusion mismatch) ultimately leading to dyspnea and hyperventilation.

In the normal, upright lung the top few centimeters of the lung termed as Zone-1 remain hypo-perfused during most of the cardiac cycle, except for ?ushes of blood during the peak ejection phase of systole. The supine position places more of the lung in zone 3 and virtually eliminates zone 1.⁽⁶⁶⁾

    No evidence of disorders known to cause platypnea-orthodeoxia was found in this patient so these symptoms probably were a result of significant areas of low or zero V/Q ratios. Severe hypoxemia can occur when many gas exchange units are not ventilated but are still perfused (creating low V/Q units that approach zero).In our patient predominantly basal part (with good perfusion and ventilation) of both lungs, were affected by the disease. It is possible that when patient is in supine position all the under-perfused upper part of lung (zone-1) converts in Zone 3 leading to equal ventilation and perfusion, ultimately adequate oxygenation. Whenever patient becomes upright, increased perfusion of poorly ventilated diseased lower zone causes ventilation perfusion mismatch leading to orthodeoxia-platypnea. The same explanation has been proposed by other authors for similar cases.^{(6,34,43,62,67)}  These low V/Q units result in a marked decrease in alveolar oxygenation and thus should evoke localized vasoconstriction. When large areas of lung parenchyma (as in our patient) are involved with V/Q imbalance of this degree, pulmonary hypertension is the usual sequel.^(68,69)

In other words, standing posture might increase blood flow to lower parts (diseased-poorly ventilated), physiological shunting may occur as deoxygenated blood may not get oxygenated because of fibrosed/destroyed lung parenchyma may not take part in oxygenation and thus exacerbating dyspnea and deoxygenation in the upright position.

In-spite of all these theories of mechanism of platypnea- orthodeoxia  syndrome, some question still remains unanswered:

(1) Why these blood gas derangements with posture did not occur in all other cases of ILD/Interstitial Fibrosis/other causes of predominant basal disease? Whether specific pathology like interstitial fibrosis or severe V/Q mismatching of any aetiology are responsible for the emergence of this platypnea- orthodeoxia syndrome remains to be clarified.

 (2) Whether the pharmacologic therapy of ILD is adequate or it requires specific therapy for this syndrome? Or simultaneous treatment of pulmonary hypertension with initial treatment of ILD would have done better?

(3) As Lung transplantation remains the only therapeutic intervention of proven bene?t in IPF, it?s to be determined also whether it cures the P-OS or not.

Further analysis of V/Q relationships in interstitial fibrosis of various aetiologies like other forms of ILD (possibly through multiple inert gas technique) may reveal the mechanism for orthodeoxia/platypnea.

Conclusion

Platypnea-orthodeoxia is a quite rare and also an underestimated syndrome, requires a high degree of suspicion. It should be considered in the differential diagnosis of dyspnea and refractory hypoxemia. Intracardiac shunts in the form of PFO/ASD and anatomic pulmonary vascular shunts e.g.AVM, are the most common etiologic associations. However, if a detailed examination including contrast echocardiography reveals no obvious intracardiac or intrapulmonary shunting combined with extensive pulmonary lesions particularly in basal areas, then severe V/Q mismatching can be considered as the probable explanation.

Abbreviations: ILD-Interstitial lung disease, IPF- Idiopathic pulmonary fibrosis, HRCT-High resolution computed tomography, A-a O₂- Alveolar arterial O2 gradient, P-OS - Platypnea-orthodeoxia syndrome.

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

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

RT was the main author who also carried out the pulmonary investigation of the case and responsible for conception & design, drafting the article, literature search and manuscript preparation. RB was the corresponding author, also responsible for manuscript editing, revising it critically for important intellectual content and final approval of the version to be published.AA and VJ were responsible for data acquisition, analysis and their interpretation and proof reading of manuscript.

LEARNING POINTS/TAKE HOME MESSAGES:

Ø  (1) It is crucial to determine the aetiology of platypnea/orthodeoxia and its adequate management

Ø  (2) Also the finding of orthodeoxia does not always imply large anatomic correctable shunts e.g. intra-cardiac shunt as previously thought.

Ø  (3) Therapeutic approach may be tested  by resection of, or flow occlusion to, localized diseased segments functioning as large areas of low or zero VA/Q to divert more perfusion to well ventilated healthy lung parts.

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