Discussion
Due to resource limitations, other differential diagnosis like pneumonia could not be ruled out with a guarantee in any of the cases. However, many symptoms, examination findings, young age, absence of significant past medical history more importantly, ultrasonography findings suggesting pulmonary edema along with rapid improvement in symptoms and oxygen saturation within a very short period of oxygen in all three patients make a strong case favoring the diagnosis of HAPE.
Certain preventive measures can be applied to minimize the modifiable risks of HAPE: gradual ascent (via vascular remodeling) [2, 8, 9] and Nifedipine (via reduction in pulmonary artery pressure) [2, 7, 8, 9] and with moderated exertion. However, certain non-modifiable risk factors, especially those attributable to higher pulmonary artery pressure [12], stronger hypoxic pulmonary vasoconstriction [12], reduced nitric oxide [13], inappropriate sympathetic response [13], congenital heart defects (e.g. patent foramen ovale) have their own share of hidden role in causing HAPE. Hypoxic pulmonary vasoconstriction response primarily functions to reduce the ventilation-perfusion mismatch created by a diseased lung segment. It, however, also works as the main pathophysiological phenomenon behind HAPE. In the background of individual risk factors, regional variability in response to pan-hypoxia [14, 15, 16], and stress failure of capillaries [1] makes some individuals more susceptible to this non-inflammatory, non-cardiogenic exudative edema.[17]
Hypoxic vasoconstriction of some arteries shifts the pressure to other arteries. Adaptation involves remodeling of such arteries over the period of hours to days so that the downstream capillaries are protected from damage due to redirected pressure. This remodeling usually gets completed within 5 days. [5, 6, 18] However, few case reports, including a case series of eight patients have described delayed onset HAPE where symptoms began after 5 days. [19] While there is no clear explanation for such a phenomenon, few hypotheses attribute the triggers to risk factors related to individual physiological differences, infection [20] and overexertion [21], which overcome the protection provided by proper acclimatization. [19, 22] It can also be hypothesized that individuals susceptible to delayed onset HAPE might either have a slower pulmonary vascular remodeling process at high altitude or have underlying congenital defects that could create a physiological base where a single ‘push factor’ in the form of infection, overexertion, etc. could trigger HAPE. The high recurrence rate of HAPE in individuals with a history of HAPE further supports the interplay of underlying individual risk factors. [23] Re-entry HAPE among highlanders shows that the previously obtained adaptive features can reverse upon migration away from the hypoxic high-altitude environment. [24]
In our series, even though the first and the second case patients had no evident features suggestive of respiratory infection; in the background of their probable physiological susceptibility, overexertion led to a rise in cardiac output and pulmonary artery pressure. The increase in these two parameters probably served as a trigger for HAPE. [25] Impairment of their alveolar ENaC channels in response to hypoxia and hypothermia could have played a role as well. [26]
In our third case, preceding pulmonary injury due to infection probably predisposed the affected lung towards HAPE. Pre-existing ventilation-perfusion mismatch along with endothelial stress leading to impaired fluid clearance must have played a significant role in the development of HAPE isolated to a single lung.
In all three cases, POCUS has played an important part in the diagnosis. It can provide an objective measure of a patient’s response to treatment as in our third case. However, the correlation between clinical and ultrasonography findings during the course of treatment needs to be studied.
Conclusion :
Diagnosis of HAPE can get challenging when it deviates from the course of its natural history. Association to over-exertion or respiratory illness can contribute to such a phenomenon. The threshold for diagnosis and treatment should be lowered in a resource-limited setting, especially in young adults presenting with a dubious picture, who have minimal risk factors for other acute lung diseases. POCUS is a great asset for early diagnosis of HAPE in resource-limited settings. Its role in HAPE monitoring needs to be explored further.