Platypnoea-orthodeoxia syndrome: novel cause for a known condition

Abstract

A 50-year-old man presented with dyspnoea while sitting, standing and walking but resolved completely in supine position. On cardiorespiratory examinations, fine crackles were noted over bibasal area. Chest X-ray showed bilateral reticulonodular shadows, restrictive pattern on spirometry, elevated alveolar arterial O₂ gradient on arterial blood gas. High-resolution CT of the thorax revealed pattern as ‘confident’ or ‘certain’ radiographic diagnosis of idiopathic pulmonary fibrosis (IPF). Bubble-contrast echocardiography in recumbent, sitting and upright positions revealed no intracardiac (right to left shunt) or intrapulmonary shunts. This case highlights the necessity of awareness of this syndrome in cases of interstitial lung diseases (ILDs) also. Although 188 cases have been described thus far of platypnoea-orthodeoxia syndrome (P-OS) of various aetiologies, to the best of our knowledge, it is the first ever case of P-OS in ILD/IPF. Both lung bases were predominantly affected in this patient, platypnoea and orthodeoxia were attributed to areas of low/zero ventilation/perfusion (V/Q) ratio (zone 1 phenomena) as no other obvious explanation was found.

Background

Platypnoea-orthodeoxia syndrome (P-OS) is a rare syndrome characterised by clinically observable dyspnoea 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.

The terms ‘platypnoea’ and ‘orthodeoxia’ were accepted in 1969 and 1976, respectively to describe the manifestations of this syndrome.^{1 2}

Till now more than 188 cases³ of this syndrome have been described in the literature, first reported in 1949 by Burchell et al.⁴ It may result from several cardiopulmonary processes with interatrial communications being the most common aetiology^5–7 and some isolated case reports of various aetiologies. Interatrial communication is so common aetiology that now it is also regarded as ‘Platypnea Orthodeoxia Disease’.³

The precise mechanism for the platypnoea and orthodeoxia is still unknown even after more than 60 years of this entity first being 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 platypnoea and orthodeoxia in a case of interstitial lung disease (ILD), with no evidence of intracardiac/intrapulmonary shunts or other known causes of P-OS.

Case presentation

A 50-year-old male farmer presented to our outpatient department with dramatic symptoms of severe respiratory distress that was present only while sitting, standing and walking. He slumped onto the floor of our outpatient department and we rushed to check his oxygen saturation (SpO₂) with a pulse oximeter that showed marked hypoxia which gradually recovered while he was supine on the floor.

We further noticed that in the sitting posture, the 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. He was unable to tolerate the standing posture for more than a few minutes. SpO₂ reached 78% after 3 min of standing and the patient could not stand anymore because of severe dyspnoea. His general physical examination findings on admission revealed: consciousness, clarity, digital clubbing, cyanosis, peripheral oedema, pallor, icterus, jugular venous distension, mucocutaneous telangiectasias and spider naevi were absent; body temperature 35.7°C; blood pressure 130/80 mm Hg in supine position and there was no significant postural drop in blood pressure; pulse rate, 90 bpm, 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 anteroposterior view. Apart from wrist joint involvement, all other joint examinations were within normal limits.

This fall in SpO₂ was associated with simultaneous increase in respiratory rate. SpO₂, tachycardia and tachypnoea did not improve with the administration of supplementary oxygen in supine, sitting as well as standing positions. Ambulation did not lead to further drops in blood saturation.

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

The patient was almost all right 6 months ago with no significant medical history including no childhood illnesses, no history of respiratory, liver or cardiac disease. Illness started with occasional dry cough and breathlessness on exertion that increased with time. Since 1 month he has developed fever, cough with expectoration, decreased appetite and arthralgia/myalgia for which he received anti tubercular treatment (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 (summarised in table 1).

Table 1.

Laboratory data on admission

Haematology	Normal range	Biochemistry	Normal range	Serology	Normal range
White blood cell 4.3×109/L Polymorphs 75% Lymphocytes 23% Eosinophils 2%	4–10×109/L	Glucose Fasting 78 mg% Postprandial 85 mg%	70–110 mg% <140 mg%	C reactive protein 4.2 mg/dL	3–12 mg/dL
Red blood cells 3.23×1012	3.5–5.5×1012	Total bilirubin 0.46(0.34+0.12)mg%	0.2–1 mg%	HIV 1 and 2	Negative
Haemoglobin 8.7 g/dL	11–16 g/dL	Serum protein 5.9 mg%	6.2–8.4 mg%	Antinuclear antibody 9.19 U	<20 U
Haematocrit 26.9%	37–54%	AST/ALT 15/19 IU/L	10–45 IU/L
Platelet 174×109/L	100–300×109/L	Alkaline phosphatase 45 IU/L	<115 IU/L	RA factor negative	Negative
Absolute eosinophil count 150/mm3	40–500/mm3	Serum creatinine 1.1 mg%	0.7–1.4 mg%
Others Sputum AFB, Gram stain, culture—negative for pathogenic organism, commensal flora grown		Blood urea 16.4 mg%	10–40 mg%	Creatinine phosphokinase 182 U/L	<171 U/L
		Uric acid 4.7 mg%	3.4–7 mg%
		Serum electrolyte Ca 1.11 mmol/L Na 131 mmol/L K 3.7 mmol/L	Ca 1.12–1.32 Na 135–148 K 3.5–4.5	HBsAg/HCV negative

AFB, acid-fast bacilli; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Ca, calcium; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; K, potassium; Na, sodium; RA, rheumatoid arthritis.

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

Figure 1.

Posteroanterior view of the chest X-ray showing bilateral diffuse interstitial infiltrates and few reticulonodular shadows in lower and mid zones.

Figure 2.

X-ray of the hands showing partial loss of joint space between carpal bones of distal row.

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

ECG demonstrated sinus rhythm with a normal axis.

Resting arterial blood gas (ABG) analysis (on supine position under room air) revealed mild hypoxaemia with respiratory alkalosis: pH 7.427; partial pressure of carbon dioxide 33.1 mm Hg; plasma saturation 57.4 mm Hg; arterial oxygen saturation (SaO₂) 90% and alveolar arterial O₂ gradient 51.2 mm Hg (increased); showing mild oxygenation failure. The patient did not allow for ABG while standing and walking (exercise) because of respiratory distress.

On pulmonary function testing: spirometry showed restrictive pattern with increased forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio of 100% with decreased FEV1 1.85 L; 70% and FVC 2.35 L; 67%.

CT of the 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 (subpleural) honeycombing were also noted. The radiologist reported these high-resolution CT patterns as ‘confident’ or ‘certain’ radiographic diagnosis of idiopathic pulmonary fibrosis (IPF) without knowledge of history of the patient. The pulmonary vasculature was also normal, with no evidence of pulmonary emboli or arteriovenous malformations (AVMs; figure 3).

Figure 3.

High-resolution CT of the thorax showing peripheral patchy predominantly subpleural, and bibasilar reticular opacities with minimal ground-glass opacities. Bilateral interstitial septal thickening, subpleural fibrosis with traction bronchiectasis and multiple peripherally arranged (subpleural) honeycombing also seen.

A transthoracic echocardiogram was performed with the patient in the supine and upright positions. Mildly enlarged right atrium and right ventricle were noted. Tricuspid regurgitation jet velocity gradient was 18 mm Hg and 32 mm Hg 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 intracardiac or intrapulmonary shunts in supine and standing positions (see figure 4 and video 1). No evidence of pericardial effusion, constrictive pericarditis was found on echocardiography.

Figure 4.

Still image from bubble-contrast echocardiography showing no right-to-left shunting of bubbles.

Video 1

Bubble Contrast Echocardiography demonstrating absence of intra-cardiac or intrapulmonary shunts in both supine and standing position.

Pulmonary angiogram was not performed due to the respiratory distress.

Right heart catheterisation facility was not available at our centre to assess right atrial pressures/pulmonary arterial hypertension.

Differential diagnosis

Causes of ILD:

1. Secondary to rheumatoid arthritis

2. IPF

Treatment

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

Outcome and follow-up

The patient responded slightly after 7 days of therapy, amount of fall in SaO₂ in sitting posture decreased but there was no major improvement in platypnoea. With 14 days of combination therapy the patient was tolerating standing posture better than previously. Therapy was continued and he was asked to come for follow-up after 2 weeks but he did not come rather he came after 3 weeks with hypovolaemic shock (acute gastroenteritis (GE) following food poisoning) and respiratory failure and died in spite of all resuscitative measures and ventilator support. Attendants of the patient told that he was doing well with prednisolone–azathioprine before this episode of acute GE.

Discussion

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

Three primary mechanisms have been postulated for this rare clinical phenomenon: intracardiac shunting, anatomic pulmonary vascular shunting and ventilation–perfusion mismatching/pulmonary parenchymal shunts^{2 5 8} with interatrial communications being the most common aetiological association.^{6 9 10}

Platypnoea and orthodeoxia have been described in several cardiopulmonary disorders categorised as¹¹

1. Cardiovascular: Intracardiac shunts,¹² patent foramen ovale (PFO),^{5 13} atrial septal defect (ASD) 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 dilation²⁶ and 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 apnoea 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} and cryptogenic fibrosing alveolitis.⁴⁰

3. Hepatic: Laennec’s cirrhosis/hepatopulmonary syndrome and portopulmonary hypertension.⁴¹

4. Infectious: Hydatid cyst,⁴² cytomegovirus and pneumocystis jiroveci infection.⁴³

5. Neurological: Parkinson's disease³⁶ and 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 bronchopleural fistula,⁵⁰ fat embolism,⁵¹ propafenone overdose in Ebstein anomaly,⁵² osteoporosis and severe kyphosis,⁵³ diabetic autonomic neuropathy,⁵⁴ progressive autonomic failure⁵⁵ and acute organophosphorus poisoning.⁵⁶

Further investigation should be focused on the detection of probable intracardiac 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.^57–59 The appearance of the contrast into the left chambers is evidence for intracardiac shunt, if early (within 3 heartbeats), and extracardiac shunt, if delayed (after 6 cardiac cycles).^{5 59–61} Moreover, this technique can image intrathoracic malformations.⁶¹ Although even pulmonary angiographic techniques are incapable of detecting multiple small arteriovenous communications.⁶²

Orthodeoxia noted in pulmonary condition has different mechanism than intracardiac 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 COPD, and in hepatic cirrhosis also; occurs due to gravitational effects, thereby increasing the shunt.^{1 37 63}

Altman and Robin¹ and Glazier et al⁶⁴ described the existence of preferential increased basilar blood flow compared with the apical regions secondary to effects of gravity (enlargement of zone 1) 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 1 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 flow (ventilation–perfusion mismatch) ultimately leading to dyspnoea and hyperventilation.

In the normal, upright lung the top few centimetres of the lung termed as zone 1 remain hypoperfused during most of the cardiac cycle, except for flushes of blood during the peak ejection phase of systole. The supine position places more of the lung in zone 3 and virtually eliminates zone 1.⁶⁵

No evidence of disorders known to cause platypnoea-orthodeoxia was found in this patient so these symptoms probably were a result of significant areas of low or zero V/Q ratios. Severe hypoxaemia 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 the patient is in supine position all the underperfused upper part of lung (zone 1) converts in zone 3 leading to equal ventilation and perfusion, ultimately adequate oxygenation. Whenever the patient becomes upright, increased perfusion of poorly ventilated diseased lower zone causes ventilation perfusion mismatch leading to platypnoea-orthodeoxia. The same explanation has been proposed by other authors for similar cases.^{6 34 43 62 66} These low V/Q units result in a marked decrease in alveolar oxygenation and thus should evoke localised 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.^{67 68}

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 dyspnoea and deoxygenation in the upright position.

In spite of all these theories of mechanism of P-OS, some questions still remain unanswered:

1. Why did these blood gas derangements with posture 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 P-OS remains to be clarified.

2. Is the pharmacological therapy of ILD adequate or does it require specific therapy for this syndrome? Or would simultaneous treatment of pulmonary hypertension with initial treatment of ILD have carried out better?

3. As lung transplantation remains the only therapeutic intervention of proven benefit in IPF, it is 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 techniques) may reveal the mechanism for orthodeoxia/platypnoea.

Conclusion

Platypnoea-orthodeoxia is a quite rare and also an underestimated syndrome and requires a high degree of suspicion. It should be considered in the differential diagnosis of dyspnoea and refractory hypoxaemia. Intracardiac shunts in the form of PFO/ASD and anatomic pulmonary vascular shunts, for example, AVM, are the most common aetiological 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.

Learning points.

• It is crucial to determine the aetiology of platypnoea/orthodeoxia and its adequate management.

• Also the finding of orthodeoxia does not always imply large anatomic correctable shunts, for example, intracardiac shunts as previously thought.

• Therapeutic approach may be tested by the resection of, or flow occlusion to, localised diseased segments functioning as large areas of low or zero VA/Q to divert more perfusion to well-ventilated healthy lung parts.