TITLE OF CASE

Platypnea-Orthodeoxia syndrome: a new cause for old disease

SUMMARY :

A 50-year-old man presented with dyspnea in sitting, standing and while walking but resolved completely in supine position. On cardiorespiratory examinations, fine crackles noted over bibasal area. Chest X-Ray showed bilateral reticulonodular shadows, restrictive pattern on spirometry, elevated A-a O2 on ABG.  HRCT thorax revealed pattern as “con?dent” or “certain” radiographic diagnosis of IPF.  Bubble contrast echocardiography in recumbent, sitting and upright positions revealed no intra-cardiac (right to left shunt) or intra-pulmonary shunts. This case highlights the necessity of awareness of this syndrome in cases of interstitial lung diseases also. Although 188 cases have been described thus far of platypnea-orthodeoxia syndrome of various etiologies, to the best of our knowledge, it is first ever case of P-OS in ILD/IPF. Both lung bases were predominantly affected in this patient, platypnea and orthodeoxia were attributed to areas of low/zero ventilation/perfusion (V/Q) ratio as no other obvious explanation was found.

Key Words: Platypnea- orthodeoxia syndrome, ILD, ventilation perfusion ratio

BACKGROUND:

Platypnea orthodeoxia syndrome (P-OS) is a rare syndrome characterized by clinically observable dyspnea and oxygen desaturation accompanying a change to a sitting or standing posture from a recumbent position, and it is resolved when the patient is supine.

Terms ‘platypnea’ and ‘orthodeoxia’ were accepted in 1969 and 1976 to describe the manifestations of this syndrome. ^[1,2]

Till now more than 188 cases ^[3] have been described in literature after this syndrome, first reported in 1949 by Burchell et al. ^[4]. It may result from a number of cardiopulmonary processes with interatrial communications being the most common aetiology ^{[5, 6, 7]} and some isolated case reports of various etiologies. Interatrial communication is so common etiology that now it is also regarded as “Platypnea Orthodeoxia Disease.” ^{[ 3]}

The precise mechanism for both the platypnea and orthodeoxia is still unknown even after more than 60 years of this entity first reported. In different isolated case reports, various mechanisms are often postulated to whatever special features were found in those particular patients.  We present a patient with severe platypnea and orthodeoxia in a case of Interstitial lung disease, with no evidence of intracardiac/intrapulmonary shunt or other known causes of P-OS.

CASE PRESENTATION :

It was a hot afternoon of April when a 50-year-old man entered in our OPD with complaints of severe respiratory distress and went flat over the floor. After lying down over floor and meanwhile we assessed blood oxygen saturation (Spo2); patient was quite comfortable. When pulse oxymetry probe was put over right index finger, showed SpO2 reading of 95%. His other vital signs were normal. He was noted to be quite comfortable while supine, but quickly tired when he attempted to stand or walk. On gross examination no sign of any cardiorespiratory illness was found and at first instance we thought of a psychiatric problem or malingering. We advised him to get admitted for further evaluation and asked him to go by walking to indoors but patient refused for walk and even to stand as he felt that he becomes breathless while he stands up.  Again we examined for any postural hypotension and presence of any cardiorespiratory finding, but apart from bilateral fine basal creptitation, cardiorespiratory examination was normal but most importantly patient was too dyspneic to  even sit for 5min and stand for 2-3 minutes. Then patient was monitored for any fall in SpO2 with the change of posture and ambulation. Yes,...…. When patient went in sitting position from lying down position, after 2-3 min saturation started to fall and reached 87% after 5 min of sitting and patient could not sit beyond that period. Patient was again made comfortable by allowing him to become flat over bed. After some time when lying down saturation was 96% on room air, we instructed patient to stand up and the patient was unable to tolerate standing posture for more than few minutes. SpO2 started to fall being 78% after 3 min of standing and patient couldn’t stand anymore because of severe dyspnoea(Fig1). This fall in oxygen saturation was associated with simultaneous increase in respiratory rate. Oxygen saturation, tachycardia and tachypnea didn’t improve with administration of supplementary oxygen in supine, sitting as well standing positions. Ambulation did not lead to further drops in blood saturation. Patient could walk with some distress but for same time for which he could stand still with almost equal fall of oxygen saturation. Ambulatory oxygen monitoring revealed that his blood oxygen would drop to 76% within three minute after of walk, that didn’t improve even with face mask oxygen. Similarly, rest while standing did not lead to recovery of his blood saturation: only return to a supine position led to recovery.

Then detailed history revealed that patient was almost all right 6 months back when he noticed occasional dry cough and breathlessness on exertion that increased with time. Since last 1 month he developed fever and expectoration, decreased appetite and arthralgia/myalgia for that he received ATT but with no improvement. Arthralgia was associated with slight morning stiffness.

He had a no significant past medical history including history from childhood, no history of respiratory, liver or cardiac disease, no history or evidence of COPD or chronic liver disease. Patient had no history of Haemoptysis, chest pain and blunt chest wall trauma. No past history of any drug intake that my lead to condition of immunosuppression, surgery including lung surgery or any exposure of radiation, contact with pets or specific industrial/inhalational exposure. He was an occasional smoker but regular tobacco chewer. He was farmer by occupation. He had no particular family medical history and he belonged to a middle class family.

His physical examination findings on admission were as follows: 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 almost same in standing posture128/80mmHg. 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. 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.

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. Diaphragmatic outlines were indistinct on both side, the cardiothoracic ratio was approximately 40%. X-Ray hands showed erosion over bilateral metacarpal joints.

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 didn’t 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% .

Condition associated with immunosuppression including his HIV, HBsAg, HCV status was negative.

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 alongwith right oblique fissure, Multiple peripherally arranged (subpleural) 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).(Fig2)

A transthoracic echocardiogram was performed with the patient in both the supine and upright positions.Mildly enlarged right atrium and right ventricle were 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 (Fig3). 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. Rheumatoid Arthritis

           2. Idiopathic Pulmonary Fibrosis

TREATMENT :

Considering the finding of arthralgia nonspecific and typical HRCT finding suggestive of Idiopathic Pulmonary Fibrosis, we started the therapy with 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 well 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.

Although the etiology for this rare clinical phenomenon of orthodeoxia-platypnea has not been clearly elucidated, three primary mechanisms have been postulated: intra-cardiac shunting, anatomic pulmonary vascular shunting, and ventilation-perfusion mismatching/pulmonary parenchymal shunts ^{(5, 2, 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 as¹¹-

1. Cardiovascular– Intracardiac shunts,¹² patent foramen ovale,^5,13   atrialseptal defect and atrial septal aneurysm,^14,15,16   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^38,39,16 cryptogenic fibrosing alveolitis⁴⁰.

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

Dyspnea (Platypnea) was chief complain and orthodeoxia was a major finding of his illness, further investigation focused on the detection of probable intra-cardiac or intrapulmonary shunts using contrast echocardiography, 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.^60,61,62  Contrast echocardiography with intravenous injection of microbubbles (agitated saline) is a sensitive test for RLS; 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). ^5,62,68,69   Moreover, this technique can image intrathoracic malformations⁶⁹. Although even pulmonary angiographic techniques are incapable of detecting multiple small arterio-venous communications.⁶³

Platypnea-orthodeoxia is the result of right to left shunting. These shunts have been classified into pulmonary parenchymal, vascular, and cardiac.⁶³ The exact mechanism for the postural changes in Pao2 in these conditions is not fully understood. Different theories have been postulated for various aetiologies.

The main cause of cardiac shunting is patent foramen ovale, that is usually asymptomatic but may be opened by the various factors and accentuated by upright posture, leads to intracardiac right to left shunting.^5,13

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 occurs through gravitational effects, thereby increasing the shunt. Dilated basal arterio-venous channels, which function in the same manner, have been implicated in the rare instances where orthodeoxia has been documented in patients with severe chronic obstructive pulmonary disease(COPD),and in hepatic cirrhosis.^1,37,64

Robin and colleagues² described three patients with P-OS, two with liver disease, and one with congenital arterio-venous malformations, noting that gravity increased blood flow through the lung bases and, therefore, increased shunting.

Two patients with interstitial fibrosis and P-OS were described by Tenholder et al. Based on a poor response to breathing 100% O₂, these authors postulated the existence of vascular shunts, suggested by early activity of tracer in brain and kidney during perfusion lung scanning in one patient but pulmonary angiography ruled out any anatomic vascular shunts.³⁴

In pulmonary shunting, the mechanism of platypnea-orthodeoxia is thought to be caused by the effects of gravity upon positional changes, causing increased basal pulmonary blood flow which, in-turn, increases flow through basal pulmonary shunts.¹

Fox and colleagues⁵⁵ described a patient with mild obstructive lung disease and P-OS occurring in orthostatic hypotension and progressive autonomic failure, which responded to fluid administration. They hypothesized the existence of a large zone I phenomenon, resulting from postural pulmonary hypoperfusion while upright, magnifying the effects of basilar ventilation-perfusion mismatch. Evidence of shunt was not found.

Papiris and colleagues²⁹ noted the occurrence of platypnea-orthodeoxia in amiodarone-induced lung damage and again attributed the postural effect to the basilar predominance of the pulmonary infiltrates.

Khan and Parekh³⁰ noted reversible P-OS during recovery from the adult respiratory distress syndrome. Pneumatoceles associated with necrotizing pneumonia involving the lower lobes were noted; response to breathing 100% O₂ excluded true shunt.

Michel O et al⁶⁷ noted deleterious effect of the sitting position on regional ventilation-perfusion matching in patients of Chronic obstructive pulmonary disease (COPD)   who experience severe dyspnea and a decreased PaO ₂ in the sitting position and improved in the supine position by using an isotopic method.  Platypnea but no orthodeoxia occurred in a COPD patient during subacute Ileus, which rapidly resolved after resolution of the ileus. Impaired abdominal muscle contraction in the upright position secondary to the ileus was thought to be responsible for the development of platypnea.⁴⁸

Tumors of the upper airway (eg, laryngeal carcinoma) may produce platypnea because of positional compression or occlusion of airways or vascular structures.⁴⁵

In cases of predominately basilar lung disease and chronic obstructive lung disease, assumption of the upright posture exacerbated ventilation-perfusion mismatch. The patient's upright posture resulted in an enlargement of zone I as suggested by Altman and Robin.¹

Altman et al¹ and Glazier JB⁵⁷ et al described the existence of preferential increased basilar blood ?ow compared with the apical regions secondary to effects of gravity. 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. Ultimately, this can result in a decrease in pulmonary artery pressures and pulmonary capillary compression resulting in respiratory death through a decrease in blood ?ow.

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. Zone 2 is the next-lower zone, blood ?ow increases regularly with distance down the lung. Below zone 2 is another zone of increasing blood ?ow, zone 3. It is to be noted that zones are a functional rather than anatomic division; instead of being ?xed topographically, they vary in vertical height according posture of subject. The supine position places more of the lung in zone 3 and virtually eliminates zone 1.⁵⁸

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.^{6,34,43,59,63}  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. Severe hypoxemia and orthodeoxia, in the absence of hypoxic pulmonary vasoconstriction (HPV), as in our patients may indicate a failure of local vasoconstrictive control, also observed by other authors as well.^34,65,66

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.

Altman and Robin¹ described that in various lung diseases, alveolar pressures become substantially elevated as a result of alterations of ventilatory mechanics (diffuse Zone I phenomenon). It is proposed that the assumption of an upright posture would increase this tendency, especially in the apical parts of the lung, because of a drop in pulmonary artery pressure, leading to pulmonary capillary compression. The combination of both the phenomena could lead to the cessation of blood flow, resulting in a respiratory dead space ultimately leading to dyspnea and hyperventilation.

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?

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.

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 and carried out the pulmonary investigation of the case. RB is the corresponding author and was responsible for manuscript preparation.

LEARNING POINTS/TAKE HOME MESSAGES:

Ø  (1)It is crucial to determine the aetiology of platypnea/orthodeoxia and its adequate management that may lead to recovery, as in our case (partial recovery).

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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FIGURE/VIDEO CAPTIONS

[a.]

PATIENT’S PERSPECTIVE :

In this tuberculosis prevalent country, patient, his relatives and his primary physician all were considering tuberculosis as a cause of chronic cough and breathlessness. They reported to our centre as he was not getting relief of symptoms and platypnea-orthodeoxia was not discovered until he presented to us.